Human plasma kallikrein inhibitors

ABSTRACT

Disclosed are compounds of formula I, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also provided are pharmaceutical compositions comprising at least one compound of the invention, and methods involving use of the compounds and compositions of the invention in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is the U.S. national stage of International PatentApplication No. PCT/US2016/054619, filed Sep. 30, 2016, which claims thebenefit of priority to U.S. Provisional Patent Application Ser. No.62/235,754, filed Oct. 1, 2015, the contents of both of which are herebyincorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

Serine proteases make up the largest and most extensively studied groupof proteolytic enzymes. Their critical roles in physiological processesextend over such diverse areas as blood coagulation, fibrinolysis,complement activation, reproduction, digestion, and the release ofphysiologically active peptides. Many of these vital processes beginwith cleavage of a single peptide bond or a few peptide bonds inprecursor protein or peptides. Sequential limited proteolytic reactionsor cascades are involved in blood clotting, fibrinolysis, and complementactivation. The biological signals to start these cascades can becontrolled and amplified as well. Similarly, controlled proteolysis canshut down or inactivate proteins or peptides through single bondcleavages.

Kallikreins are a subgroup of serine proteases. In humans, plasmakallikrein (KLKB1) has no known homologue, while tissuekallikrein-related peptidases (KLKs) encode a family of fifteen closelyrelated serine proteases. Plasma kallikrein participates in a number ofpathways relating to the intrinsic pathway of coagulation, inflammation,and the complement system.

Coagulation is the process by which blood forms clots, for example tostop bleeding. The physiology of coagulation is somewhat complex insofaras it includes two separate initial pathways, which converge into afinal common pathway leading to clot formation. In the final commonpathway, prothrombin is converted into thrombin, which in turn convertsfibrinogen into fibrin, the latter being the principal building block ofcross-linked fibrin polymers which form a hemostatic plug. Of the twoinitial pathways upstream of the final common pathway, one is known asthe contact activation or intrinsic pathway, and the other is known asthe tissue factor or extrinsic pathway.

The intrinsic pathway begins with formation of a primary complex oncollagen by high-molecular-weight kininogen (HMWK), prekallikrein, andFXII (Factor XII; Hageman factor). Prekallikrein is converted tokallikrein, and FXII is activated to become FXIIa. FXIIa then convertsFactor XI (FXI) into FXIa, and FXIa in turn activates Factor IX (FIX),which with its co-factor FVIIIa form the “tenase” complex, whichactivates Factor X (FX) to FXa. It is FXa which is responsible for theconversion of prothrombin into thrombin within the final common pathway.

Prekallikrein, the inactive precursor of plasma kallikrein, issynthesized in the liver and circulates in the plasma bound to HMWK oras a free zymogen. Prekallikrein is cleaved by activated factor XII(FXIIa) to release activated plasma kallikrein (PK). Activated plasmakallikrein displays endopeptidase activity towards peptide bonds afterarginine (preferred) and lysine. PK then generates additional FXIIa in afeedback loop which in turn activates factor XI (FXI) to FXIa to connectto the common pathway. Although the initial activation of the intrinsicpathway is through a small amount of FXIIa activating a small amount ofPK, it is the subsequent feedback activation of FXII by PK that controlsthe extent of activation of the intrinsic pathway and hence downstreamcoagulation. Hathaway, W. E., et al. (1965) Blood 26:521-32.

Activated plasma kallikrein also cleaves HMWK to release the potentvasodilator peptide bradykinin. It is also able to cleave a number ofinactive precursor proteins to generate active products, such as plasmin(from plasminogen) and urokinase (from prourokinase). Plasmin, aregulator of coagulation, proteolytically cleaves fibrin into fibrindegradation products that inhibit excessive fibrin formation.

Patients who have suffered acute myocardial infarction (MI) showclinical evidence of being in a hypercoagulable (clot-promoting) state.This hypercoagulability is paradoxically additionally aggravated inthose receiving fibrinolytic therapy. Increased generation of thrombin,as measured by thrombin-antithrombin III (TAT) levels, is observed inpatients undergoing such treatment compared to the already high levelsobserved in those receiving heparin alone. Hoffmeister, H. M. et al.(1998) Circulation 98:2527-33. The increase in thrombin has beenproposed to result from plasmin-mediated activation of the intrinsicpathway by direct activation of FXII by plasmin.

Not only does the fibrinolysis-induced hypercoagulability lead toincreased rates of reocclusion, but it is also probably responsible, atleast in part, for failure to achieve complete fibrinolysis of the clot(thrombus), a major shortcoming of fibrinolytic therapy (Keeley, E. C.et al. (2003) Lancet 361: 13-20). Another problem in fibrinolytictherapy is the accompanying elevated risk of intracranial hemorrhage.Menon, V. et al. (2004) Chest 126:549S-575S; Fibrinolytic TherapyTrialists' Collaborative Group (1994) Lancet 343:311-22. Hence, anadjunctive anti-coagulant therapy that does not increase the risk ofbleeding, but inhibits the formation of new thrombin, would be greatlybeneficial.

Therefore, a need exists to develop additional inhibitors of PK that cantip the balance of fibrinolysis/thrombosis at the occluding thrombustoward dissolution, thereby promoting reperfusion and attenuating thehypercoagulable state, thus preventing the thrombus from reforming andreoccluding the vessel.

SUMMARY OF THE INVENTION

In certain aspects, the invention provides compounds of formula (I), andpharmaceutically acceptable salts thereof:

wherein, independently for each occurrence:

-   R¹ represents —OH, —OR^(c), —NH₂, —NHR^(c), —NR^(c)R^(d), alkyl,    aryl, aralkyl, heteroaryl, heteroaralkyl, halo, haloalkyl,    cycloalkyl, (cycloalkyl)alkyl, —C(O)R^(c), —C(O)OH, —C(O)OR^(c),    —OC(O)R^(c), —C(O)NH₂, —C(O)NHR^(c), —C(O)NR^(c)R^(d), —NHC(O)R^(c),    or —NR^(c)C(O)R^(d); or two geminal occurrences of R¹ taken together    with the carbon to which they are attached represent —C(O)—; or two    vicinal or geminal occurrences of R¹ taken together form an    optionally substituted fused or spirocyclic carbocyclic or    heterocyclic ring;-   W is a bond, —C(O)NH—, —C(O)N(R^(c))—, —C(O)O—, —CH₂—, or —C(O)—;-   R² represents optionally substituted aryl, heteroaryl, aralkyl,    heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl), or    (heterocycloalkyl)alkyl;-   V represents optionally substituted aryl or heteroaryl;-   Z is absent or represents one or more substituents independently    selected from the group consisting of halo, haloalkyl, —NO₂, —CN,    —C(O)R^(c), —C(O)OH, —C(O)OR^(c), —OC(O)R^(c), —C(O)NH₂,    —C(O)NHR^(c), —C(O)NR^(c)R^(d), —NHC(O)R^(c), —N(R^(c))C(O)R^(d),    —OS(O)_(p)(R^(c)), —NHS(O)_(p)(R^(c)), and —NR^(c)S(O)_(p)(R^(c));-   X represents —C(NH₂)—, —C(NH(R^(c)))—, —C(NR^(c)R^(d))—,    —C(NHS(O)_(p)R^(c))—, —C(NHC(O)R^(c))—, —C(NHC(O)NH₂)—,    —C(NHC(O)NHR^(c))—, —C(NHC(O)NR^(c)R^(d))—, —C(OH)—, —C(O(alkyl))-,    —C(N₃)—, —C(CN)—, —C(NO₂)—, —C(S(O)_(n)R^(a))—, —C[—C(═O)R^(c)]—,    —C[—C(═O)NR^(c)R^(d)]—, —C[—C(═O)SR^(c)]—, —C[—S(O)R^(c)]—,    —C[—S(O)₂R^(c)]—, —C[S(O)(OR^(c))]—, —C[—S(O)₂(OR^(c))]—,    —C[—SO₂NR^(c)R^(d)]—, —C(halogen)-, —C(alkyl),    —C((cycloalkyl)alkyl), —C(alkenyl)-, —C(alkynyl)-, or —C(aralkyl)-;-   R³ represents optionally substituted aryl, heteroaryl, cycloalkyl,    or heterocycloalkyl;-   R^(3a) is absent or represents one or more substituents    independently selected from the group consisting of halo, hydroxy,    alkyl, —CF₃, —OCF₃, alkoxy, aryl, heteroaryl, aryloxy, amino,    aminoalkyl, —C(O)NH₂, cyano, —NHC(O)alkyl, —SO₂alkyl, —SO₂NH₂,    cycloalkyl, —(CH₂)_(r)OR^(a), —NO₂, —(CH₂)_(r)NR^(a)R^(b),    —(CH₂)_(r)C(O)R^(a), —NR^(a)C(O)R^(b), —C(O)NR^(c)R^(d),    —NR^(a)C(O)NR^(c)R^(d), —C(═NR^(a))NR^(c)R^(d),    —NHC(═NR^(a))NR^(c)R^(d), —NR^(a)R^(b), —SO₂NR^(c)R^(d),    —NR^(a)SO₂NR^(c)R^(d), —NR^(a)SO₂alkyl, —NR^(a)SO₂R^(a),    —S(O)_(p)R^(a), —(CF₂)_(r)CF₃, —NHCH₂R^(a), —OCH₂R^(a), —SCH₂R^(a),    —NH(CH₂)₂(CH₂)_(r)R^(a), —O(CH₂)₂(CH₂)_(r)R^(a), or    —S(CH₂)₂(CH₂)_(r)R^(a);-   Y represents a bond; or —Y—R⁴ represents optionally substituted    -alkylene-R⁴, —CH₂C(O)—R⁴, —CH₂NH—R⁴, —CH₂N(alkyl)-R⁴,    —CR^(a)R^(b)—R⁴, —NH—R⁴, —NHCH₂—R⁴, —NHC(O)—R⁴, —N(alkyl)-R⁴,    —N(alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴, —N((cycloalkyl)alkyl)R⁴,    -heterocyclyl-R⁴, —OR⁴, —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b),    —SCH₂R4, or —SR⁴;-   R⁴ represents hydrogen, hydroxy, optionally substituted alkyl,    cycloalkyl, (heterocycloalkyl)alkyl, (cycloalkyl)alkyl, —CH₂OH,    —CH(alkyl)OH, —CH(NH₂)CH(alkyl)₂, aryl, aralkyl, heteroaryl,    heteroaralkyl, —CH₂S(alkyl), amino, or cyano; or    —(CR^(a)R^(b))_(r)(CR^(a)R^(b))_(p)— fused to the 4-position of the    ring bearing Z to form a 5- to 7-membered heterocyclic ring with    optional substituents; or,-   when R³ is phenyl, R⁴ can represent —NR^(a)— fused to the position    ortho to X on that phenyl;-   each R^(a) and R^(b) is independently H, alkyl, alkenyl, alkynyl,    aralkyl, (cycloalkyl)alkyl, —C(═O)R^(c), —C(═O)OR^(c),    —C(═O)NR^(c)R^(d), —C(═O)SR^(c), —S(O)R^(c), —S(O)₂R^(c),    —S(O)(OR^(c)), or —SO₂NR^(c)R^(d);-   R^(c) and R^(d) represent, independently for each occurrence,    optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aryl,    aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl,    heterocycloalkyl, (heterocycloalkyl)alkyl, —C(O)alkyl, or    —S(O)_(p)(alkyl); or R^(c) and R^(d) can be taken together to form    an optionally substituted heterocyclic ring;

can represent

-   r is 0, 1, 2, or 3;-   n is an integer from 0 to 6; and-   p is 0, 1, or 2.

In certain aspects, the invention provides a pharmaceutical composition,comprising a compound of the invention, or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier.

In certain aspects, the invention provides a method of treating orpreventing a disease or condition characterized by unwanted plasmakallikrein activity. The method comprises the step of administering to asubject in need thereof a therapeutically effective amount of a compoundof the invention, or a pharmaceutically acceptable salt thereof, therebytreating or preventing the disease or condition characterized byunwanted plasma kallikrein activity. In one embodiment, the disease orcondition characterized by unwanted plasma kallikrein activity isselected from the group consisting of stroke, inflammation, reperfusioninjury, acute myocardial infarction, deep vein thrombosis, postfibrinolytic treatment condition, angina, edema, angioedema, hereditaryangioedema, sepsis, arthritis, hemorrhage, blood loss duringcardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus,retinopathy, diabetic retinopathy, diabetic macular edema, diabeticmacular degeneration, age-related macular edema, age-related maculardegeneration, proliferative retinopathy, neuropathy, hypertension, brainedema, increased albumin excretion, macroalbuminuria, and nephropathy.

DETAILED DESCRIPTION

Inhibitors of plasma kallikrein have been reported and are useful intherapeutic methods and compositions suitable for use in eliminating orreducing various forms of ischemia, including but not limited toperioperative blood loss, cerebral ischemia, the onset of systemicinflammatory response, and/or reperfusion injury, e.g., reperfusioninjury associated with cerebral ischemia or a focal brain ischemia.Perioperative blood loss results from invasive surgical procedures thatlead to contact activation of complement components and thecoagulation/fibrinolysis systems. Kallikrein inhibitors can be used toreduce or prevent perioperative blood loss and a systemic inflammatoryresponse in patients subjected to invasive surgical procedures,especially cardiothoracic surgeries. Kallikrein inhibitors can also beused to reduce or prevent cerebral ischemia and stroke, and/orreperfusion injury associated with cerebral ischemia. They can alsoprevent neurological and cognitive deficits associated with stroke,blood loss, and cerebral ischemia, e.g., events that are not associatedwith surgical intervention. Further examples of applications forkallikrein inhibitors include pediatric cardiac surgery, lungtransplantation, total hip replacement, and orthotopic livertransplantation, to reduce or prevent stroke during these procedures, aswell as to reduce or prevent stroke during coronary artery bypassgrafting (CABG) and extracorporeal membrane oxygenation (ECMO).

Definitions

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “heteroatom” is art-recognized and refers to an atom of anyelement other than carbon or hydrogen. Illustrative heteroatoms includeboron, nitrogen, oxygen, phosphorus, sulfur and selenium, andalternatively oxygen, nitrogen or sulfur.

The term “alkyl” as used herein is a term of art and refers to saturatedaliphatic groups, including straight-chain alkyl groups, branched-chainalkyl groups, cycloalkyl (alicyclic) groups, alkyl substitutedcycloalkyl groups, and cycloalkyl substituted alkyl groups. In certainembodiments, a straight-chain or branched-chain alkyl has about 30 orfewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chain,C₃-C₃₀ for branched chain), and alternatively, about 20 or fewer, or 10or fewer. In certain embodiments, the term “alkyl” refers to a C₁-C₁₀straight-chain alkyl group. In certain embodiments, the term “alkyl”refers to a C₁-C₆ straight-chain alkyl group. In certain embodiments,the term “alkyl” refers to a C₃-C₁₂ branched-chain alkyl group. Incertain embodiments, the term “alkyl” refers to a C₃-C₈ branched-chainalkyl group. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term “cycloalkyl” means mono- or bicyclic or bridged saturatedcarbocyclic rings, each having from 3 to 12 carbon atoms. Certaincycloalkyls have from 5-12 carbon atoms in their ring structure, and mayhave 6-10 carbons in the ring structure. Preferably, cycloalkyl is(C₃-C₇)cycloalkyl, which represents a monocyclic saturated carbocyclicring, having from 3 to 7 carbon atoms. Examples of monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicycliccycloalkyl ring systems include bridged monocyclic rings and fusedbicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkylring where two non-adjacent carbon atoms of the monocyclic ring arelinked by an alkylene bridge of between one and three additional carbonatoms (i.e., a bridging group of the form —(CH₂)_(w)—, where w is 1, 2,or 3). Representative examples of bicyclic ring systems include, but arenot limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain amonocyclic cycloalkyl ring fused to either a phenyl, a monocycliccycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or amonocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl isattached to the parent molecular moiety through any carbon atomcontained within the monocyclic cycloalkyl ring. Cycloalkyl groups areoptionally substituted. In certain embodiments, the fused bicycliccycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused toeither a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclicheterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein thefused bicyclic cycloalkyl is optionally substituted.

The term “cycloalkylalkyl” as used herein refers to an alkyl groupsubstituted with one or more cycloalkyl groups. An example ofcycloalkylalkyl is cyclohexylmethyl group.

The term “heterocyclyl” as used herein refers to a radical of anon-aromatic ring system, including, but not limited to, monocyclic,bicyclic, and tricyclic rings, which can be completely saturated orwhich can contain one or more units of unsaturation, for the avoidanceof doubt, the degree of unsaturation does not result in an aromatic ringsystem, and having 3 to 12 atoms including at least one heteroatom, suchas nitrogen, oxygen, or sulfur. For purposes of exemplification, whichshould not be construed as limiting the scope of this invention, thefollowing are examples of heterocyclic rings: aziridinyl, azirinyl,oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl,1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl,diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl,dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, isoxazolyl,azepines, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl,oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. A heterocyclylgroup is optionally substituted by one or more substituents as describedbelow.

The term “heterocycloalkylalkyl” as used herein refers to an alkyl groupsubstituted with one or more heterocycloalkyl (i.e., heterocyclyl)groups.

The term “alkenyl” as used herein means a straight or branched chainhydrocarbon radical containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.The unsaturated bond(s) of the alkenyl group can be located anywhere inthe moiety and can have either the (Z) or the (E) configuration aboutthe double bond(s).

The term “alkynyl” as used herein means a straight or branched chainhydrocarbon radical containing from 2 to 10 carbon atoms and containingat least one carbon-carbon triple bond. Representative examples ofalkynyl include, but are not limited, to acetylenyl, 1-propynyl,2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “alkylene” is art-recognized, and as used herein pertains to adiradical obtained by removing two hydrogen atoms of an alkyl group, asdefined above. In one embodiment an alkylene refers to a disubstitutedalkane, i.e., an alkane substituted at two positions with substituentssuch as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic orheteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, orthe like. That is, in one embodiment, a “substituted alkyl” is an“alkylene”.

The term “amino” is a term of art and as used herein refers to bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R_(a), R_(b), and R_(c) each independently represent a hydrogen,an alkyl, an alkenyl, —(CH₂)_(x)—R_(d), or R_(a) and R_(b), takentogether with the N atom to which they are attached complete aheterocycle having from 4 to 8 atoms in the ring structure; R_(d)represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or apolycyclyl; and x is zero or an integer in the range of 1 to 8. Incertain embodiments, only one of R_(a) or R_(b) may be a carbonyl, e.g.,R_(a), R_(b), and the nitrogen together do not form an imide. In otherembodiments, R_(a) and R_(b) (and optionally R_(c)) each independentlyrepresent a hydrogen, an alkyl, an alkenyl, or —(CH₂)_(x)—R^(d). Incertain embodiments, the term “amino” refers to —NH₂.

The term “amido”, as used herein, means —NHC(═O)—, wherein the amidogroup is bound to the parent molecular moiety through the nitrogen.Examples of amido include alkylamido such as CH₃C(═O)N(H)— andCH₃CH₂C(═O)N(H)—.

The term “acyl” is a term of art and as used herein refers to any groupor radical of the form RCO— where R is any organic group, e.g., alkyl,aryl, heteroaryl, aralkyl, and heteroaralkyl. Representative acyl groupsinclude acetyl, benzoyl, and malonyl.

The term “aminoalkyl” as used herein refers to an alkyl groupsubstituted with one or more one amino groups. In one embodiment, theterm “aminoalkyl” refers to an aminomethyl group.

The term “aminoacyl” is a term of art and as used herein refers to anacyl group substituted with one or more amino groups.

The term “aminothionyl” as used herein refers to an analog of anaminoacyl in which the O of RC(O)— has been replaced by sulfur, hence isof the form RC(S)—.

The term “phosphoryl” is a term of art and as used herein may in generalbe represented by the formula:

wherein Q50 represents S or O, and R59 represents hydrogen, a loweralkyl or an aryl; for example, —P(O)(OMe)- or —P(O)(OH)₂. When used tosubstitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkylmay be represented by the general formulas:

wherein Q50 and R59, each independently, are defined above, and Q51represents O, S or N; for example, —O—P(O)(OH)OMe or —NH—P(O)(OH)₂. WhenQ50 is S, the phosphoryl moiety is a “phosphorothioate.”

The term “aminophosphoryl” as used herein refers to a phosphoryl groupsubstituted with at least one amino group, as defined herein; forexample, —P(O)(OH)NMe₂.

The term “azide” or “azido”, as used herein, means an —N₃ group.

The term “carbonyl” as used herein refers to —C(═O)—.

The term “thiocarbonyl” as used herein refers to —C(═S)—.

The term “alkylphosphoryl” as used herein refers to a phosphoryl groupsubstituted with at least one alkyl group, as defined herein; forexample, —P(O)(OH)Me.

The term “alkylthio” as used herein refers to alkyl-S—.

The term “carboxy”, as used herein, means a —CO₂H group.

The term “aryl” is a term of art and as used herein refers to includesmonocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, forexample, benzene, naphthalene, anthracene, and pyrene. The aromatic ringmay be substituted at one or more ring positions with one or moresubstituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromaticor heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano,or the like. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings (the rings are “fused rings”) wherein at leastone of the rings is an aromatic hydrocarbon, e.g., the other cyclicrings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls. In certain embodiments, the term“aryl” refers to a phenyl group. In certain embodiments, “aryl” has from6 to 10 carbon atoms.

The term “heteroaryl” is a term of art and as used herein refers to amonocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 totalatoms including one or more heteroatoms such as nitrogen, oxygen, orsulfur in the ring structure. Exemplary heteroaryl groups includeazaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl,furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl,isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl,oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl,pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl,pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl,thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl,thienyl, thiomorpholinyl, triazolyl or tropanyl, and the like. The“heteroaryl” may be substituted at one or more ring positions with oneor more substituents such as halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino,amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether,alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl,aromatic or heteroaromatic moieties, fluoroalkyl (such astrifluromethyl), cyano, or the like. The term “heteroaryl” also includespolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings (the rings are “fusedrings”) wherein at least one of the rings is an aromatic group havingone or more heteroatoms in the ring structure, e.g., the other cyclicrings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls.

The term “aralkyl” or “arylalkyl” is a term of art and as used hereinrefers to an alkyl group substituted with an aryl group, wherein themoiety is appended to the parent molecule through the alkyl group.

The term “heteroaralkyl” or “heteroarylalkyl” is a term of art and asused herein refers to an alkyl group substituted with a heteroarylgroup, appended to the parent molecular moiety through the alkyl group.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxycarbonyl” means an alkoxy group, as defined herein,appended to the parent molecular moiety through a carbonyl group,represented by —C(═O)—, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkylcarbonyl”, as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “arylcarbonyl”, as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of arylcarbonylinclude, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

The term “alkylcarbonyloxy” and “arylcarbonyloxy”, as used herein, meansan alkylcarbonyl or arylcarbonyl group, as defined herein, appended tothe parent molecular moiety through an oxygen atom. Representativeexamples of alkylcarbonyloxy include, but are not limited to, acetyloxy,ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples ofarylcarbonyloxy include, but are not limited to phenylcarbonyloxy.

The term “alkenoxy” or “alkenoxyl” means an alkenyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkenoxyl include, but are not limited to,2-propen-1-oxyl (i.e., CH₂═CH—CH₂—O—) and vinyloxy (i.e., CH₂═CH—O—).

The term “aryloxy” as used herein means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.

The term “heteroaryloxy” as used herein means a heteroaryl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom.

The term “carbocyclyl” as used herein means a monocyclic or multicyclic(e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3to 12 carbon atoms that is completely saturated or has one or moreunsaturated bonds, and for the avoidance of doubt, the degree ofunsaturation does not result in an aromatic ring system (e.g., phenyl).Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl,2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and2-cyclopentenylmethyl.

The term “cyano” is a term of art and as used herein refers to —CN.

The term “halo” is a term of art and as used herein refers to —F, —Cl,—Br, or —I.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, wherein some or all of the hydrogens are replaced with halogenatoms.

The term “hydroxy” is a term of art and as used herein refers to —OH.

The term “hydroxyalkyl”, as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “silyl”, as used herein, includes hydrocarbyl derivatives ofthe silyl (H₃Si—) group (i.e., (hydrocarbyl)₃Si—), wherein a hydrocarbylgroups are univalent groups formed by removing a hydrogen atom from ahydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl groups can becombinations of differing groups which can be varied in order to providea number of silyl groups, such as trimethylsilyl (TMS),tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS),triisopropylsilyl (TIPS), and [2-(trimethyl silyl)ethoxy]methyl (SEM).

The term “silyloxy”, as used herein, means a silyl group, as definedherein, is appended to the parent molecule through an oxygen atom.

Certain compounds contained in compositions of the present invention mayexist in particular geometric or stereoisomeric forms. In addition,compounds of the present invention may also be optically active. Thepresent invention contemplates all such compounds, including cis- andtrans-isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers,(L)-isomers, the racemic mixtures thereof, and other mixtures thereof,as falling within the scope of the invention. Additional asymmetriccarbon atoms may be present in a substituent such as an alkyl group. Allsuch isomers, as well as mixtures thereof, are intended to be includedin this invention.

If, for instance, a particular enantiomer of compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,fragmentation, decomposition, cyclization, elimination, or otherreaction.

The term “substituted” is also contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissiblesubstituents include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic substituents oforganic compounds. Illustrative substituents include, for example, thosedescribed herein above. The permissible substituents may be one or moreand the same or different for appropriate organic compounds. Forpurposes of this invention, the heteroatoms such as nitrogen may havehydrogen substituents and/or any permissible substituents of organiccompounds described herein which satisfy the valences of theheteroatoms. This invention is not intended to be limited in any mannerby the permissible substituents of organic compounds.

The phrase “protecting group”, as used herein, means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991). Protected forms of the inventive compounds are included withinthe scope of this invention.

For purposes of the invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

Other chemistry terms herein are used according to conventional usage inthe art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms(ed. Parker, S., 1985), McGraw-Hill, San Francisco, incorporated hereinby reference). Unless otherwise defined, all technical and scientificterms used herein have the same meaning as commonly understood by one ofordinary skill in the art to which this invention pertains.

The term “pharmaceutically acceptable salt” as used herein includessalts derived from inorganic or organic acids including, for example,hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric,formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic,salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic,trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and otheracids. Pharmaceutically acceptable salt forms can include forms whereinthe ratio of molecules comprising the salt is not 1:1. For example, thesalt may comprise more than one inorganic or organic acid molecule permolecule of base, such as two hydrochloric acid molecules per moleculeof compound of Formula I. As another example, the salt may comprise lessthan one inorganic or organic acid molecule per molecule of base, suchas two molecules of compound of Formula I per molecule of tartaric acid.

The terms “carrier” and “pharmaceutically acceptable carrier” as usedherein refer to a diluent, adjuvant, excipient, or vehicle with which acompound is administered or formulated for administration. Non-limitingexamples of such pharmaceutically acceptable carriers include liquids,such as water, saline, and oils; and solids, such as gum acacia,gelatin, starch paste, talc, keratin, colloidal silica, urea, and thelike. In addition, auxiliary, stabilizing, thickening, lubricating,flavoring, and coloring agents may be used. Other examples of suitablepharmaceutical carriers are described in Remington's PharmaceuticalSciences by E. W. Martin, herein incorporated by reference in itsentirety.

The term “treat” as used herein means prevent, halt or slow theprogression of, or eliminate a disease or condition in a subject. In oneembodiment “treat” means halt or slow the progression of, or eliminate adisease or condition in a subject. In one embodiment, “treat” meansreduce at least one objective manifestation of a disease or condition ina subject.

The term “effective amount” as used herein refers to an amount that issufficient to bring about a desired biological effect.

The term “therapeutically effective amount” as used herein refers to anamount that is sufficient to bring about a desired therapeutic effect.

The term “inhibit” as used herein means decrease by an objectivelymeasurable amount or extent. In various embodiments “inhibit” meansdecrease by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95percent compared to relevant control. In one embodiment “inhibit” meansdecrease 100 percent, i.e., halt or eliminate.

The term “subject” as used herein refers to a mammal. In variousembodiments, a subject is a mouse, rat, rabbit, cat, dog, pig, sheep,horse, cow, or non-human primate. In one embodiment, a subject is ahuman.

Compounds

The present invention provides compounds of Formula (I), orpharmaceutically acceptable salts thereof:

wherein, independently for each occurrence:

-   R¹ represents —OH, —OR^(c), —NH₂, —NHR^(c), —NR^(c)R^(d), alkyl,    aryl, aralkyl, heteroaryl, heteroaralkyl, halo, haloalkyl,    cycloalkyl, (cycloalkyl)alkyl, —C(O)R^(c), —C(O)OH, —C(O)OR^(c),    —OC(O)R^(c), —C(O)NH₂, —C(O)NHR^(c), —C(O)NR^(c)R^(d), —NHC(O)R^(c),    or —NR^(c)C(O)R^(d); or two geminal occurrences of R¹ taken together    with the carbon to which they are attached represent —C(O)—; or two    vicinal or geminal occurrences of R¹ taken together form an    optionally substituted fused or spirocyclic carbocyclic or    heterocyclic ring;-   W is a bond, —C(O)NH—, —C(O)N(R^(c))—, —C(O)O—, —CH₂—, or —C(O)—;-   R² represents optionally substituted aryl, heteroaryl, aralkyl,    heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl), or    (heterocycloalkyl)alkyl;-   V represents optionally substituted aryl or heteroaryl;-   Z is absent or represents one or more substituents independently    selected from the group consisting of halo, haloalkyl, —NO₂, —CN,    —C(O)R^(c), —C(O)OH, —C(O)OR^(c), —OC(O)R^(c), —C(O)NH₂,    —C(O)NHR^(c), —C(O)NR^(c)R^(d), —NHC(O)R^(c), —N(R^(c))C(O)R^(d),    —OS(O)_(p)(R^(c)), —NHS(O)_(p)(R^(c)), and —NR^(c)S(O)_(p)(R^(c));-   X represents —C(NH₂)—, —C(NH(R^(c)))—, —C(NR^(c)R^(d))—,    —C(NHS(O)_(p)R^(c))—, —C(NHC(O)R^(c))—, —C(NHC(O)NH₂)—,    —C(NHC(O)NHR^(c))—, —C(NHC(O)NR^(c)R^(d))—, —C(OH)—, —C(O(alkyl))-,    —C(N₃)—, —C(CN)—, —C(NO₂)—, —C(S(O)_(n)R^(a))—, —C[—C(═O)R^(c)]—,    —C[—C(═O)NR^(c)R^(d)]—, —C[—C(═O)SR^(c)]—, —C[—S(O)R^(c)]—,    —C[—S(O)₂R^(c)]—, —C[S(O)(OR^(c))]—, —C[—S(O)₂(OR^(c))]—,    —C[—SO₂NR^(c)R^(d)]—, —C(halogen)-, —C(alkyl),    —C((cycloalkyl)alkyl), —C(alkenyl)-, —C(alkynyl)-, or —C(aralkyl)-;-   R³ represents optionally substituted aryl, heteroaryl, cycloalkyl,    or heterocycloalkyl;-   R^(3a) is absent or represents one or more substituents    independently selected from the group consisting of halo, hydroxy,    alkyl, —CF₃, —OCF₃, alkoxy, aryl, heteroaryl, aryloxy, amino,    aminoalkyl, —C(O)NH₂, cyano, —NHC(O)alkyl, —SO₂alkyl, —SO₂NH₂,    cycloalkyl, —(CH₂)_(r)OR^(a), —NO₂, —(CH₂)_(r)NR^(a)R^(b),    —(CH₂)_(r)C(O)R^(a), —NR^(a)C(O)R^(b), —C(O)NR^(d),    —NR^(a)C(O)NR^(c)R^(d), —C(═NR^(a))NR^(c)R^(d),    —NHC(═NR^(a))NR^(c)R^(d), —NR^(a)R^(b), —SO₂NR^(c)R^(d),    —NR^(a)SO₂NR^(c)R^(d), —NR^(a)SO₂alkyl, —NR^(a)SO₂R^(a),    —S(O)_(p)R^(a), —(CF₂)_(r)CF₃, —NHCH₂R^(a), —OCH₂R^(a), —SCH₂R^(a),    —NH(CH₂)₂(CH₂)_(r)R^(a), —O(CH₂)₂(CH₂)_(r)R^(a), or    —S(CH₂)₂(CH₂)_(r)R^(a);-   Y represents a bond; or —Y—R⁴ represents optionally substituted    -alkylene-R⁴, —CH₂C(O)—R⁴, —CH₂NH—R⁴, —CH₂N(alkyl)-R⁴,    —CR^(a)R^(b)—R⁴, —NH—R⁴, —NHCH₂—R⁴, —NHC(O)—R⁴, —N(alkyl)-R⁴,    —N(alkyl)CH₂—R⁴, —N((CH₂)₂OH)—R⁴, —N((cycloalkyl)alkyl)R⁴,    -heterocyclyl-R⁴, —OR⁴, —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b),    —SCH₂R4, or —SR⁴;-   R⁴ represents hydrogen, hydroxy, optionally substituted alkyl,    cycloalkyl, (heterocycloalkyl)alkyl, (cycloalkyl)alkyl, —CH₂OH,    —CH(alkyl)OH, —CH(NH₂)CH(alkyl)₂, aryl, aralkyl, heteroaryl,    heteroaralkyl, —CH₂S(alkyl), amino, or cyano; or    —(CR^(a)R^(b))_(r)(CR^(a)R^(b))_(p)— fused to the 4-position of the    ring bearing Z to form a 5- to 7-membered heterocyclic ring with    optional substituents; or,-   when R³ is phenyl, R⁴ can represent —NR^(a)— fused to the position    ortho to X on that phenyl;-   each R^(a) and R^(b) is independently H, alkyl, alkenyl, alkynyl,    aralkyl, (cycloalkyl)alkyl, —C(═O)R^(c), —C(═O)OR^(c),    —C(═O)NR^(c)R^(d), —C(═O)SR^(c), —S(O)R^(c), —S(O)₂R^(c),    —S(O)(OR^(c)), or —SO₂NR^(c)R^(d);-   R^(c) and R^(d) represent, independently for each occurrence,    optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aryl,    aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl,    heterocycloalkyl, (heterocycloalkyl)alkyl, —C(O)alkyl, or    —S(O)_(p)(alkyl); or R^(c) and R^(d) can be taken together to form    an optionally substituted heterocyclic ring;

can represent

-   r is 0, 1, 2, or 3;-   n is an integer from 0 to 6; and-   p is 0, 1, or 2.

In certain embodiments, R¹ represents —OH, —OR^(c), —NH₂, —NHR^(c),—NR^(c)R^(d), alkyl, aryl, heteroaryl, halo, haloalkyl, cycloalkyl,—OC(O)R^(c), —NHC(O)R^(c), or —NR^(c)C(O)R^(d); or two geminaloccurrences of R¹ taken together with the carbon to which they areattached represent —C(O)—; or two vicinal or geminal occurrences of R¹taken together form an optionally substituted fused or spirocycliccarbocyclic or heterocyclic ring.

In certain embodiments, R¹ represents —OH, —OR^(c), —NH₂, alkyl, aryl,halo, haloalkyl, cycloalkyl, or —OC(O)R^(c).

In certain embodiments, n is 1.

In certain such embodiments, R¹ represents —OH or —OR^(c).

In certain embodiments wherein n is 1, R¹ represents —OR^(c), forexample R¹ may represent —O((C₁-C₆)alkyl).

In certain embodiments wherein n is 1, R¹ represents —OC(O)R^(c), forexample R¹ may represent —OC(O)((C₁-C₆)alkyl).

In certain embodiments, R¹ represents —NH₂.

In certain embodiments, R¹ represents (C₁-C₆)alkyl.

In certain embodiments, n is 2.

In certain such embodiments, the two occurrences of R¹ are geminal,i.e., the two occurrences of R¹ are attached to the same carbon atom.

In certain such embodiments, one occurrence of R¹ represents —OH or—OR^(c); and the other occurrence of R¹ represents aryl or heteroaryl.

Alternatively, in other certain such embodiments, one occurrence of R¹represents —OH or —OR^(c); and the other occurrence of R¹ representshaloalkyl.

In yet another alternative embodiment, both of the two geminaloccurrences of R¹ are halo.

In certain embodiments, the two geminal occurrences of R¹ taken togetherwith the carbon to which they are attached represent —C(O)—.

In certain embodiments wherein n is 2, the two occurrences of R¹ arevicinal, i.e., the two occurrences of R¹ are attached to two adjacentcarbon atoms.

In certain such embodiments, the two vicinal occurrences of R¹ takentogether form an optionally substituted fused carbocyclic ring.

In certain embodiments, n is 0.

In certain embodiments, W is —C(O)NH— or —C(O)N(R^(c))—.

In certain such embodiments, R² represents optionally substituted arylor heteroaryl.

In certain embodiments, R² represents aryl or heteroaryl, substituted byone or more substituents selected from the group consisting of —OH,halo, —NH₂, —NH((C₁-C₆)alkyl), —N((C₁-C₆)alkyl)₂, —CN, —NO₂,(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, —C(O)OH,—C(O)O(C₁-C₆)alkyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, and—C(O)N((C₁-C₆)alkyl)₂.

In certain embodiments wherein W is —C(O)NH— or —C(O)N(R^(c))—, R²represents (halo)aryl or (halo)heteroaryl.

In certain embodiments, W is —C(O)—.

In certain such embodiments, R² represents optionally substitutedaralkyl or heteroaralkyl.

In certain embodiments, V represents optionally substituted aryl.

In certain embodiments, Z represents one or more substituentsindependently selected from the group consisting of halo, haloalkyl,—NO₂, and —CN.

In certain embodiments, Z represents one instance of halo.

In certain embodiments, Z represents one instance of fluoro.

In certain embodiments, Z is absent.

In certain embodiments, X represents —C(NH₂)—, —C(NH(R^(c)))—,—C(NR^(c)R^(d))—, —C(NHS(O)_(p)R^(c))—, —C(NHC(O)R^(c))—,—C(NHC(O)NH₂)—, —C(NHC(O)NHR^(c))—, or —C(NHC(O)NR^(c)R^(d))—.

In certain embodiments, X represents —C(NH₂)—, —C(NH(R^(c)))—,—C(NR^(c)R^(d))—, —C(NHS(O)_(p)R^(c))—, —C(NHC(O)R^(c))—, or—C(NHC(O)NHR^(c))—.

In certain embodiments, X represents —C(NH₂)—.

In certain embodiments, X represents —C(NH(R^(c)))—.

In certain such embodiments, X represents —C(NH(cycloalkyl)alkyl)-. Inalternative such embodiments, X represents —C(NH(C₁-C₆)alkyl)-.

In certain embodiments, X represents —C(NHS(O)_(p)R^(c))—.

In certain such embodiments, X represents —C(NHS(O)_(p)(C₁-C₆)alkyl)-,wherein p is 1 or 2.

In certain embodiments, X represents —C(NHC(O)NHR^(c))—.

In certain such embodiments, X represents optionally substituted—C(NHC(O)NH(aryl))- or C(NHC(O)NH(heteroaryl))-.

In certain embodiments, X represents —C(NHC(O)R^(c))—.

In certain such embodiments, X represents —C(NHC(O)((C₁-C₆)alkyl))-.

In certain embodiments, R³ represents optionally substituted aryl orheteroaryl.

In certain embodiments, R³ represents optionally substituted heteroaryl.

In certain such embodiments, R³ represents pyridyl.

In certain embodiments, R³ represents optionally substituted aryl.

In certain such embodiments, R³ represents phenyl, optionallysubstituted by one or more substituents selected from the groupconsisting of —CN, halo, —NO₂, (C₁-C₆)alkyl, and (C₁-C₆)haloalkyl.

In certain embodiments, R^(3a) is absent or represents halo, alkyl,—CF₃, —OCF₃, aryl, heteroaryl, —C(O)NH₂, cyano, —NHC(O)alkyl, —SO₂alkyl,—SO₂NH₂, —NO₂, —NR^(a)C(O)R^(b), —C(O)NR^(c)R^(d),—NR^(a)C(O)NR^(c)R^(d), —C(═NR^(a))NR^(c)R^(d),—NHC(═NR^(a))NR^(c)R^(d), —SO₂NR^(c)R^(d), —NR^(a)SO₂NR^(c)R^(d),—NR^(a)SO₂alkyl, —NR^(a)SO₂R^(a), —S(O)_(p)R^(a), or —(CF₂)_(r)CF₃.

In certain embodiments, Y represents a bond.

In certain embodiments, R⁴ represents H.

In certain embodiments, R⁴ represents (cycloalkyl)alkyl. For examples,R⁴ may represent (cyclopropyl)(C₁-C₆)alkyl.

In certain embodiments, the compound of the invention is selected fromthe following table of compounds, or a pharmaceutically acceptable saltthereof:

Pharmaceutical Compositions

The invention provides pharmaceutical compositions, each comprising oneor more compounds of the invention and a pharmaceutically acceptablecarrier. In certain embodiments, the pharmaceutical compositioncomprises a compound of the invention and a pharmaceutically acceptablecarrier. In certain embodiments, the pharmaceutical compositioncomprises a plurality of compounds of the invention and apharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition is formulated forparenteral administration.

In certain embodiments, the pharmaceutical composition is formulated fororal administration.

In certain embodiments, a pharmaceutical composition of the inventionfurther comprises at least one additional pharmaceutically active agentother than a compound of the invention. The at least one additionalpharmaceutically active agent can be an agent useful in the treatment ofa disease or condition characterized by unwanted plasma kallikreinactivity. For example, the at least one additional pharmaceuticallyactive agent can be an anticoagulation agent, an anti-platelet agent, ora thrombolytic agent.

Anticoagulation agents prevent the coagulation of blood components andthus prevent clot formation, for example in atrial fibrillation.Anticoagulants include, but are not limited to, heparin, warfarin,coumadin, dicumarol, phenprocoumon, acenocoumarol, ethyl biscoumacetate,hirudin, bivalarutin, direct thrombin inhibitors, and indandionederivatives.

Anti-platelet agents inhibit platelet aggregation and are often used toprevent thromboembolic stroke in patients who have experienced atransient ischemic attack, stroke, or atrial fibrillation. Anti-plateletagents include, but are not limited to, aspirin, thienopyridinederivatives such as ticlopodine and clopidogrel, dipyridamole, andsulfinpyrazone, as well as RGD mimetics.

Thrombolytic agents lyse clots that cause thromboembolic phenomena suchas stroke, myocardial infarction, and pulmonary thromboembolism.Thrombolytic agents include, but are not limited to, plasminogen,a2-antiplasmin, streptokinase, antistreplase, TNK, tissue plasminogenactivator (tPA), and urokinase. Tissue plasminogen activator includesnative tPA and recombinant tPA, as well as modified forms of tPA thatretain the enzymatic or fibrinolytic activities of native tPA.

Pharmaceutical compositions of the invention can be prepared bycombining one or more compounds of the invention with a pharmaceuticallyacceptable carrier and, optionally, one or more additionalpharmaceutically active agents.

Methods of Use

The present invention provides compounds that inhibit the formation ofthrombin via the intrinsic pathway and thus reduce the risk of newpathogenic thrombus formation (vessel occlusion or reocclusion) and alsoimprove fibrinolytic-induced reperfusion when given as adjunctivetherapy with a fibrinolytic regimen. Diseases and conditions that can betreated using the compounds of the present invention include, but arenot limited to, stroke, inflammation, reperfusion injury, acutemyocardial infarction, deep vein thrombosis, post fibrinolytic treatmentcondition, angina, edema, angioedema, hereditary angioedema, sepsis,arthritis, hemorrhage, blood loss during cardiopulmonary bypass,inflammatory bowel disease, diabetes mellitus, retinopathy, diabeticretinopathy, diabetic macular edema, diabetic macular degeneration,age-related macular edema, age-related macular degeneration,proliferative retinopathy, neuropathy, hypertension, brain edema,increased albumin excretion, macroalbuminuria, and nephropathy.

For example, in patients with angioedema conditions, small polypeptidePK inhibitor DX-88 (ecallantide) alleviates edema in patients withhereditary angioedema (HAE). Williams, A. et al. (2003) Transfus. Apher.Sci. 29:255-8; Schneider, L. et al. (2007) J Allergy Clin Immunol.120:416-22; and Levy, J. H. et al. (2006) Expert Opin. Invest. Drugs15:1077-90. A bradykinin B2 receptor antagonist, Icatibant, is alsoeffective in treating HAE. Bork, K. et al. (2007) J. Allergy Clin.Immunol. 119:1497-1503. Because plasma kallikrein generates bradykinin,inhibition of plasma kallikrein is expected to inhibit bradykininproduction.

For example, in coagulation resulting from fibrinolytic treatment (e.g.,treatment with tissue plasminogen activator or streptokinase), higherlevels of plasma kallikrein are found in patients undergoingfibrinolysis. Hoffmeister, H. M. et al. (1998) J. Cardiovasc. Pharmacol.31:764-72. Plasmin-mediated activation of the intrinsic pathway has beenshown to occur in plasma and blood and was markedly attenuated in plasmafrom individuals deficient in any of the intrinsic pathway components.Ewald, G. A. et al. (1995) Circulation 91:28-36.

Individuals who have had an acute MI were found to have elevated levelsof activated plasma kallikrein and thrombin. Hoffmeister, H. M., et al.(1998) Circulation 98:2527-33.

DX-88 reduced brain edema, infarct volume, and neurological deficits inan animal model of ischemic stroke. Storini, C. et al. (2006) J. Pharm.Exp. Ther. 318:849-854. C1-inhibitor reduced infarct size in a mousemodel of middle cerebral artery occlusion (MCAO). De Simoni, M. G. etal. (2004) Am. J. Pathol. 164:1857-1863; and Akita, N. et al. (2003)Neurosurgery 52:395-400). B2 receptor antagonists were found to reducethe infarct volume, brain swelling, and neutrophil accumulation and wereneuroprotective in an MCAO animal model. Zausinger, S. et al. (2003)Acta Neurochir. Suppl. 86:205-7; Lumenta, D. B. et al. (2006) Brain Res.1069:227-34; Ding-Zhou, L. et al. (2003) Br. J Pharmacol. 139:1539-47.

Regarding blood loss during cardiopulmonary bypass (CPB), it has beenfound that the kallikrein-kinin (i.e., contact) system is activatedduring CABG. Wachtfogel, Y. T. (1989) Blood 73:468. Activation of thecontact system during CPB results in up to a 20-fold increase in plasmabradykinin. Cugno, M. et al. (2006) Chest 120:1776-82; and Campbell, D.J. et al. (2001) Am. J. Physiol. Reg. Integr. Comp. Physiol.281:1059-70.

Plasma kallikrein inhibitors P8720 and PKSI-527 have also been found toreduce joint swelling in rat models of arthritis. De La Cadena, R. A. etal. (1995) FASEB J. 9:446-52; Fujimori, Y. (1993) Agents Action 39:42-8.It has also been found that inflammation in animal models of arthritiswas accompanied by activation of the contact system. Blais, C. Jr. etal. (1997) Arthritis Rheum. 40:1327-33.

Additionally, plasma kallikrein inhibitor P8720 has been found to reduceinflammation in an acute and chronic rat model of inflammatory boweldisease (IBD). Stadnicki, A. et al. (1998) FASEB J. 12:325-33;Stadnicki, A. et al. (1996) Dig. Dis. Sci. 41:912-20; and De La Cadena,R. A., et al. (1995) FASEB J. 9:446-52. The contact system is activatedduring acute and chronic intestinal inflammation. Sartor, R. B. et al.(1996) Gastroenterology 110:1467-81. It has been found that B2 receptorantagonist, an antibody to high molecular weight kininogen, or reductionin levels of kininogen reduced clinicopathology in animal models of IBD.Ibid.; Arai, Y. et al. (1999) Dig. Dis. Sci. 44:845-51; and Keith, J. C.et al. (2005) Arthritis Res. Therapy 7:R769-76.

H-D-Pro-Phe-Arg-chloromethylketone (CMK), an inhibitor of PK and FXIIand a physiological inhibitor (C1-inhibitor), has been found to reducevascular permeability in multiple organs and reduce lesions inlipopolysaccharide (LPS)- or bacterial-induced sepsis in animals. Liu,D. et al. (2005) Blood 105:2350-5; Persson, K. et al. (2000) J. Exp.Med. 192:1415-24. Clinical improvement was observed in sepsis patientstreated with C1-inhibitor. Zeerleder, S. et al. (2003) Clin. Diagnost.Lab. Immunol. 10:529-35; Caliezi, C., et al. (2002) Crit. Care Med.30:1722-8; and Marx, G. et al. (1999) Intensive Care Med. 25:1017-20.Fatal cases of septicemia are found to have a higher degree of contactactivation. Martinez-Brotons, F. et al. (1987) Thromb. Haemost.58:709-713; and Kalter, E. S. et al. (1985) J. Infect. Dis. 151:1019-27.

It has also been found that prePK levels are higher in diabetics,especially those with proliferative retinopathy, and correlate withfructosamine levels. Gao, B.-B., et al. (2007) Nature Med. 13:181-8; andKedzierska, K. et al. (2005) Archives Med. Res. 36:539-43. PrePK is alsofound to be highest in those with a sensorimotor neuropathy. Christie,M. et al. (1984) Thromb. Haemostas. (Stuttgart) 52:221-3. PrePK levelsare elevated in diabetics and are associated with increased bloodpressure. PrePK levels independently correlate with the albuminexcretion rate and are elevated in diabetics with macroalbuminuria,suggesting prePK may be a marker for progressive nephropathy. Jaffa, A.A. et al. (2003) Diabetes 52:1215-21. B1 receptor antagonists have beenfound to decrease plasma leakage in rats treated with streptozotocin.Lawson, S. R. et al. (2005) Eur. J. Pharmacol. 514:69-78. B1 receptorantagonists can also prevent streptozotocin-treated mice from developinghyperglycemia and renal dysfunction. Zuccollo, A. et al. (1996) Can. J.Physiol. Pharmacol. 74:586-9.

In certain aspects, the invention provides a compound of the invention,or a pharmaceutically acceptable salt thereof, for use as a medicament.

In certain aspects, the invention provides methods of treating orpreventing a disease or condition characterized by unwanted plasmakallikrein activity. The method includes the step of administering to asubject in need thereof a therapeutically effective amount of a compoundof the invention, or a pharmaceutically acceptable salt thereof, therebytreating or preventing the disease or condition characterized byunwanted plasma kallikrein activity. By reducing plasma kallikreinactivity in the subject, the disease or condition characterized byunwanted plasma kallikrein activity is treated.

Alternatively, in certain aspects, the invention provides a compound ofthe invention, or a pharmaceutically acceptable salt thereof, fortreatment of a disease or condition characterized by unwanted plasmakallikrein activity.

Alternatively, in certain aspects, the invention provides the use of acompound of the invention, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for use in treatment of adisease or condition characterized by unwanted plasma kallikreinactivity.

As used herein, a “disease or condition characterized by unwanted plasmakallikrein activity” refers to any disease or condition in which it isdesirable to reduce plasma kallikrein activity. For example, it may bedesirable to reduce plasma kallikrein activity in the setting of ahypercoagulable state. As another example, it may be desirable to reduceplasma kallikrein activity in the setting of tissue ischemia that isassociated with the presence or formation of thrombus.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is selected from the groupconsisting of stroke, inflammation, reperfusion injury, acute myocardialinfarction, deep vein thrombosis, post fibrinolytic treatment condition,angina, edema, angioedema, hereditary angioedema, sepsis, arthritis,hemorrhage, blood loss during cardiopulmonary bypass, inflammatory boweldisease, diabetes mellitus, retinopathy, diabetic retinopathy, diabeticmacular edema, diabetic macular degeneration, age-related macular edema,age-related macular degeneration, proliferative retinopathy, neuropathy,hypertension, brain edema, increased albumin excretion,macroalbuminuria, and nephropathy.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is angioedema.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is hereditary angioedema (HAE).

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is stroke.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is reperfusion injury.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is acute myocardial infarction.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is hemorrhage.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is blood loss during cardiopulmonarybypass.

In certain embodiments, the disease or condition characterized byunwanted plasma kallikrein activity is selected from the groupconsisting of retinopathy, diabetic retinopathy, diabetic macular edema,diabetic macular degeneration, age-related macular edema, age-relatedmacular degeneration, and proliferative retinopathy.

Formulations, Routes of Administration, and Dosing

The compounds of the invention can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient, in a variety of forms adapted to the chosen route ofadministration, e.g., orally or parenterally, by intravenous,intraperitoneal, intramuscular, topical, or subcutaneous routes.Additional routes of administration are also contemplated by theinvention.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2% to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing diluents and carriers: binders such as gum tragacanth, acacia,corn starch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water or physiologicallyacceptable aqueous solution, optionally mixed with a nontoxicsurfactant. Dispersions can also be prepared in glycerol, liquidpolyethylene glycols, triacetin, and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, methods of preparation can includevacuum drying and the freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of the invention to the skin are known in the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392; incorporatedherein by reference), Geria (U.S. Pat. No. 4,992,478; incorporatedherein by reference), Smith et al. (U.S. Pat. No. 4,559,157;incorporated herein by reference), and Wortzman (U.S. Pat. No.4,820,508; incorporated herein by reference).

Useful dosages of the compounds of the invention can be determined, atleast initially, by comparing their in vitro activity and in vivoactivity in animal models. Methods for the extrapolation of effectivedosages in mice, and other animals, to humans are known in the art; forexample, see U.S. Pat. No. 4,938,949 (incorporated herein by reference).

The amount of the compound, or an active salt thereof, required for usein treatment will vary not only with the particular compound or saltselected but also with the route of administration, the nature of thecondition being treated, and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg body weight of the recipient per day, e.g., fromabout 3 to about 90 mg/kg of body weight per day, from about 6 to about75 mg per kilogram of body weight per day, from about of 10 to about 60mg/kg of body weight per day, or from about 15 to about 50 mg/kg of bodyweight per day.

Compounds of the invention can be conveniently formulated in unit dosageform; for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500mg of active ingredient per unit dosage form. In one embodiment, theinvention provides a composition comprising a compound of the inventionformulated in such a unit dosage form. The desired dose may convenientlybe presented in a single dose or as divided doses to be administered atappropriate intervals, for example, as two, three, four or moresub-doses per day. The sub-dose itself may be further divided, e.g.,into a number of discrete loosely spaced administrations.

Compounds of the invention can also be administered in combination withother therapeutic agents, for example, other agents that are useful fortreating or preventing ischemia, blood loss, or reperfusion injury.

Other delivery systems can include time-release, delayed release, orsustained release delivery systems such as are well-known in the art.Such systems can avoid repeated administrations of the active compound,increasing convenience to the subject and the physician. Many types ofrelease delivery systems are available and known to those of ordinaryskill in the art. Use of a long-term sustained release implant may bedesirable. Long-term release, as used herein, means that the deliverysystem or is implant constructed and arranged to deliver therapeuticlevels of the active ingredient for at least 30 days, and preferably 60days.

In certain embodiments, a compound of the invention is formulated forintraocular administration, for example direct injection or insertionwithin or in association with an intraocular medical device.

The compounds of the invention may be formulated for depositing into amedical device, which may include any of a variety of conventionalgrafts, stents, including stent grafts, catheters, balloons, baskets, orother device that can be deployed or permanently implanted within a bodylumen. As a particular example, it would be desirable to have devicesand methods which can deliver compounds of the invention to the regionof a body which has been treated by interventional technique.

In exemplary embodiment, a compound of the invention may be depositedwithin a medical device, such as a stent, and delivered to the treatmentsite for treatment of a portion of the body.

Stents have been used as delivery vehicles for therapeutic agents (i.e.,drugs). Intravascular stents are generally permanently implanted incoronary or peripheral vessels. Stent designs include those of U.S. Pat.No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S.Pat. No. 4,886,062 (Wiktor). Such designs include both metal andpolymeric stents, as well as self-expanding and balloon-expandablestents. Stents may also be used to deliver a drug at the site of contactwith the vasculature, as disclosed in U.S. Pat. No. 5,102,417 (Palmaz),U.S. Pat. No. 5,419,760 (Narciso, Jr.), U.S. Pat. No. 5,429,634(Narciso, Jr.), and in International Patent Application Nos. WO 91/12779(Medtronic, Inc.) and WO 90/13332 (Cedars-Sanai Medical Center), forexample.

The term “deposited” means that the compound is coated, adsorbed,placed, or otherwise incorporated into the device by methods known inthe art. For example, the compound may be embedded and released fromwithin (“matrix type”) or surrounded by and released through (“reservoirtype”) polymer materials that coat or span the medical device. In thelatter example, the compound may be entrapped within the polymermaterials or coupled to the polymer materials using one or more thetechniques for generating such materials known in the art. In otherformulations, the compound may be linked to the surface of the medicaldevice without the need for a coating, for example by means ofdetachable bonds, and release with time or can be removed by activemechanical or chemical processes. In other formulations, the compoundmay be in a permanently immobilized form that presents the compound atthe implantation site.

In certain embodiments, the compound may be incorporated with polymercompositions during the formation of biocompatible coatings for medicaldevices, such as stents. The coatings produced from these components aretypically homogeneous and are useful for coating a number of devicesdesigned for implantation.

The polymer may be either a biostable or a bioabsorbable polymerdepending on the desired rate of release or the desired degree ofpolymer stability, but frequently a bioabsorbable polymer is preferredfor this embodiment since, unlike a biostable polymer, it will not bepresent long after implantation to cause any adverse, chronic localresponse. Bioabsorbable polymers that could be used include, but are notlimited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA),poly(lactide-co-glycolide) (PLLA/PGA), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lacticacid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly (L-lactide)(PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA/PTMC),polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoester,polyphosphoester urethane, poly(amino acids), cyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters)(e.g., PEO/PLA), polyalkylene oxalates, polyphosphazenes andbiomolecules such as fibrin, fibrinogen, cellulose, starch, collagen andhyaluronic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates,cross linked or amphipathic block copolymers of hydrogels, and othersuitable bioabsorbable poplymers known in the art. Also, biostablepolymers with a relatively low chronic tissue response such aspolyurethanes, silicones, and polyesters could be used, and otherpolymers could also be used if they can be dissolved and cured orpolymerized on the medical device such as polyolefins, polyisobutyleneand ethylene-alphaolefin copolymers; acrylic polymers and copolymers,vinyl halide polymers and copolymers, such as polyvinyl chloride;polyvinylpyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether;polyvinylidene halides, such as polyvinylidene fluoride andpolyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinylaromatics, such as polystyrene, polyvinyl esters, such as polyvinylacetate; copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyrancopolymer; polyhydroxy-propyl-methacrylamide-phenol;polyhydroxyethyl-aspartamide-phenol; polyethyleneoxide-polylysinesubstituted with palmitoyl residues; polyamides, such as Nylon 66 andpolycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes;polyimides; polyethers; epoxy resins, polyurethanes; rayon;rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate;cellulose acetate butyrate; cellophane; cellulose nitrate; cellulosepropionate; cellulose ethers; and carboxymethyl cellulose.

Polymers and semipermeable polymer matrices may be formed into shapedarticles, such as valves, stents, tubing, prostheses and the like.

In certain embodiments of the invention, the compound of the inventionis coupled to a polymer or semipermeable polymer matrix that is formedas a stent or stent-graft device.

Typically, polymers are applied to the surface of an implantable deviceby spin coating, dipping, or spraying. Additional methods known in theart can also be utilized for this purpose. Methods of spraying includetraditional methods as well as microdeposition techniques with an inkjettype of dispenser. Additionally, a polymer can be deposited on animplantable device using photo-patterning to place the polymer on onlyspecific portions of the device. This coating of the device provides auniform layer around the device which allows for improved diffusion ofvarious analytes through the device coating.

In certain embodiments of the invention, the compound is formulated forrelease from the polymer coating into the environment in which themedical device is placed. Preferably, the compound is released in acontrolled manner over an extended time frame (e.g., months) using atleast one of several well-known techniques involving polymer carriers orlayers to control elution. Some of these techniques are described inU.S. Patent Application 2004/0243225A1, the entire disclosure of whichis incorporated herein in its entirety.

Moreover, as described for example in U.S. Pat. No. 6,770,729, which isincorporated herein in its entirety, the reagents and reactionconditions of the polymer compositions can be manipulated so that therelease of the compound from the polymer coating can be controlled. Forexample, the diffusion coefficient of the one or more polymer coatingscan be modulated to control the release of the compound from the polymercoating. In a variation on this theme, the diffusion coefficient of theone or more polymer coatings can be controlled to modulate the abilityof an analyte that is present in the environment in which the medicaldevice is placed (e.g., an analyte that facilitates the breakdown orhydrolysis of some portion of the polymer) to access one or morecomponents within the polymer composition (and for example, therebymodulate the release of the compound from the polymer coating). Yetanother embodiment of the invention includes a device having a pluralityof polymer coatings, each having a plurality of diffusion coefficients.In such embodiments of the invention, the release of the compound fromthe polymer coating can be modulated by the plurality of polymercoatings.

In yet another embodiment of the invention, the release of the compoundfrom the polymer coating is controlled by modulating one or more of theproperties of the polymer composition, such as the presence of one ormore endogenous or exogenous compounds, or alternatively, the pH of thepolymer composition. For example, certain polymer compositions can bedesigned to release a compound in response to a decrease in the pH ofthe polymer composition.

Kits

The invention also provides a kit, comprising a compound of theinvention, or a pharmaceutically acceptable salt thereof: at least oneother therapeutic agent, packaging material, and instructions foradministering the compound of the invention or the pharmaceuticallyacceptable salt thereof and the other therapeutic agent or agents to amammal to treat or prevent ischemia, blood loss, or reperfusion injuryin the mammal. In one embodiment, the mammal is a human.

EXAMPLES

The present invention is further illustrated by the following examples,which in no way should be construed as limiting the scope of the claimedinvention. The entire contents of all the references (includingliterature references, issued patents, published patent applications,and co-pending patent applications) cited throughout this applicationare hereby expressly incorporated by reference.

Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(1p) Step-1: Preparation ofN-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine(1b)

To a stirred solution of 5-bromo-2-fluoroaniline (1a) (225 g, 1184 mmol)in triethylamine (3301 mL, 20 eq) was added trimethylsilyltrifluoromethanesulfonate (481 mL, 2664 mmol) at room temperature [Note:during the addition heat was generated but, was not needed to cool theflask]. The mixture was heated at reflux for 16 h and cooled to roomtemperature. The two layers were separated. [Note: try not to expose thesolution to air or moisture during the separation]. Dark bottom solutionwas discarded and the upper layer was concentrated in vacuum to removeexcess triethylamine. The oily residue was transferred to 1000 mL flaskand distilled under high vacuum. The compound starts to distill at 100°C. at 0.5 mm/Hg. First fraction (about 15 mL) was discarded the secondfraction was collected steadily at 100° C., 0.5 mm/Hg, to furnishN-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine(1b) (364 g, 1089 mmol, 92% yield). This was always freshly prepared fornext step; ¹H NMR (300 MHz, Chloroform-d) δ 7.17-7.11 (m, 1H), 7.09 (dd,J=7.5, 2.5 Hz, 1H), 6.89 (d, J=0.9 Hz, 1H), 0.08 (d, J=0.6 Hz, 18H).

Step-2: Preparation of(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c)

To magnesium turnings (33.1 g, 1361 mmol) in tetrahydrofuran (15 mL) wasadded iodine (1.381 g, 5.44 mmol) followed byN-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine(1b) (4 g) to activate the reaction for about 5 minutes (Iodine colorwas decolorized). At this point rest of the solution ofN-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine(1b) (364 g, 1089 mmol) in tetrahydrofuran (1000 mL) was added slowly inover a period of 3 h (reaction temperature was around 60° C. during theaddition. The resulting dark grey solution was stirred overnight tofurnish (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide(1c) (397 g, 1107 mmol, 102% yield, approximately 1M solution) which wasused fresh in the next step.

Step-3: Preparation of(R)-(−)-N-benzylidene-2-methylpropane-2-sulfinamide (1d)

To a stirred solution of benzaldehyde (259 mL, 2541 mmol) intetrahydrofuran (2500 mL) was added (R)-2-methylpropane-2-sulfinamide(280 g, 2310 mmol), tetraisopropoxytitanium (1382 mL, 4620 mmol) andstirred at room temperature for 36 h. The reaction mixture was dilutedwith 1 L of brine with vigorous stirring, followed by ethyl acetate (6L) and stirred for 4 h. The reaction mixture was filtered washed withethyl acetate (6×2 L). The organic layers were combined washed with asolution of sodium metabisulfite (329 mL, 1733 mmol), water (462 mL)dried over MgSO₄, filtered, evaporated to dryness. The crude residue waspurified by flash column chromatography (silica gel 1.5 kg, eluting with20% ethyl acetate in hexane) to furnish(R)-(−)-N-benzylidene-2-methylpropane-2-sulfinamide (1d) (472.51 g, 2257mmol, 98% yield) as a pale yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.57(s, 1H), 8.03-7.89 (m, 2H), 7.70-7.48 (m, 3H), 1.19 (s, 9H); MS (ES+)232.18 (M+Na); Optical rotation: [α]_(D)=(−) 112.11 [4.155, CHCl₃].

Step-4: Preparation of(R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1e) and(R)-N-((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1f)

Batch-1

To a solution of (R)-(−)-N-benzylidene-2-methylpropane-2-sulfinamide(1d) (475 g, 2269 mmol) in toluene (4 L) cooled to −11° C. was addeddropwise freshly prepared Grignard reagent(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c)(4.75 L, 3563 mmol) over a period of 70 minutes, maintaining internalbetween temp (−11.1 to −10° C.). Reaction mixture was stirred at thesame temperature until complete (check TLC for reaction completion).Reaction was quenched with 1N KHSO₄ at −10° C. The reaction was warmedto room temperature over a 30 mins period and organic layer wasseparated. The aqueous layer was extracted with ethyl acetate (2×2 L).The organic layers were combined washed water (2×2 L), brine (3.5 L),dried filtered and concentrated in vacuum to afford crude oil containingmixture of diastereoisomers of(R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1e) and(R)-N-((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1f) [(de=72/28) 727 g, 2269 mmol]. To crude in a 22 L flash was addedIPA (2000 mL) and heated at reflux with stirring (30 mins to completelysolubilize). The reaction mixture was cooled to 27° C. over a period of5 h with gentle stirring. The solid obtained was collected by filtrationwashed with IPA (5×100 mL), air dried for 24 h to furnish(R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1e) (351 g, 48.3% yield, de=94.63%.) as a white crystalline solid.

Batch-2

The above procedure was repeated using(R)-(−)-N-benzylidene-2-methylpropane-2-sulfinamide (1d) (0.500 kg,2.389 mol) to furnish(R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1e) (329 g, 43% yield, de=93.58%.) as a white crystalline solid.

Batch-3

The above procedure was repeated using(R)-(−)-N-benzylidene-2-methylpropane-2-sulfinamide (1d) (409 g, 1953mmol) to furnish(R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1e) (264 g, 42% yield, de=94.33%.) as a white crystalline solid.

Second crystallization: The above three batches were combined In a 22 Lwide mouth rotary evaporator flash fitted with a mechanical stirrercontaining mixture of diastereoisomers of (1e) and (1f) (batch-1, 351 g,48.3% yield, de=94.63%), (batch-2, 329 g, 43% yield, de=93.58%) and(batch-3, 264 g, 42% yield, de=94.33%) was added IPA (4000 mL) andheated at reflux with stirring (50 mins to completely solubilize). Thereaction mixture was cooled to room temperature overnight with gentlestirring (13° C.). The solid crystallized after about 1 h of cooling andstirring was continued overnight. The solid obtained was collected byfiltration washed with IPA (1×100 mL and 2×200 mL), dried in high vacuumfor 24 h to furnish(R)-N—((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1e) (872 g, 92% yield, de=99.2852%.) as a white crystalline solid; ¹HNMR (300 MHz, DMSO-d₆) δ 7.40-7.26 (m, 4H), 7.25-7.15 (m, 1H), 6.90 (dd,J=11.5, 8.3 Hz, 1H), 6.75 (dd, J=8.9, 2.2 Hz, 1H), 6.57 (ddd, J=8.4,4.4, 2.2 Hz, 1H), 5.77 (d, J=5.4 Hz, 1H), 5.33 (d, J=5.3 Hz, 1H), 5.11(s, 2H), 1.13 (s, 9H); ¹⁹F NMR (282 MHz, DMSO) δ −137.36; ¹³C NMR (75MHz, DMSO) δ 151.32, 148.19, 143.13, 139.74, 139.70, 128.22, 127.63,126.93, 115.04, 114.98, 114.91, 114.82, 114.60, 114.35, 61.88, 55.42,22.77; Optical rotation: [α]_(D)=(−) 70.70 (MeOH, 1.065); Analysiscalculated for C₁₇H₂₁FN₂OS: C, 63.72; H, 6.61; N, 8.74. Found: C, 63.74;H, 6.74; N, 8.74.

Data for(R)-N-((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1f); ¹H NMR (300 MHz, DMSO-d₆) δ 7.41-7.36 (m, 2H), 7.36-7.27 (m, 2H),7.26-7.18 (m, 1H), 6.89 (dd, J=11.5, 8.3 Hz, 1H), 6.71 (dd, J=8.9, 2.2Hz, 1H), 6.51 (ddd, J=8.4, 4.5, 2.2 Hz, 1H), 5.82 (d, J=5.5 Hz, 1H),5.32 (d, J=5.5 Hz, 1H), 5.09 (s, 2H, 1H D₂O exchangeable), 1.14 (s, 9H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.32; MS (ES+) 321.3 (M+1), 343.3(M+Na), 663.5 (2M+Na); MS (ES−) 319.3 (M−1). Optical rotation:[α]_(D)=(−) 73.21 (MeOH, 2.505).

Step-5: Preparation of (+)-5-(amino(phenyl)methyl)-2-fluoroaniline (1g)

To a mechanically stirred slurry of(R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1e) (99.13 g, 309 mmol) in MTBE (600 mL) was added 4M HCl (dioxane)(162 mL, 650 mmol) and stirred at room temperature for 11 h. Solidstarts forming as soon as HCl addition is started. TLC analysis showsunreacted starting material, additional 4M HCl (dioxane) (162 mL, 650mmol) was added and stirred at room temperature for 16 h. Excessmethanol was evaporated, mixture basified with 3N NaOH (455 mL) andcompound was extracted with ethyl acetate (2×750 mL). The combinedorganic layers were dried over anhydrous MgSO4, filtered, evaporated todryness. The solid was triturated with hexanes, stirred for 1 h andsolid obtained was collected by filtration to afford(+)-5-(amino(phenyl)methyl)-2-fluoroaniline (1g) (38.0 g, 57% yield) asa pale yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.39-7.33 (m, 2H), 7.27(ddd, J=7.6, 6.6, 1.2 Hz, 2H), 7.21-7.13 (m, 1H), 6.86 (dd, J=11.5, 8.3Hz, 1H), 6.77 (dd, J=9.0, 2.2 Hz, 1H), 6.54 (ddd, J=8.3, 4.4, 2.2 Hz,1H), 5.03 (s, 2H, D₂O exchangeable), 4.96 (s, 1H), 2.71 (s, 2H, D₂Oexchangeable); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −138.12; MS (ES+) 217.2(M+1); 215.1 (M−1); Optical rotation: [α]_(D)=(+) 1.47 (0.545, MeOH).

Step-6: Preparation of(−)-N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline(1h) and (−)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline(1i)

To a stirred solution of (+)-5-(amino(phenyl)methyl)-2-fluoroaniline(1g) (5.312 g, 24.56 mmol) in MeOH (80 mL) was addedcyclopropanecarboxaldehyde (1.944 mL, 25.8 mmol) at 0° C. for a periodof 10 min and stirred for 30 mins. To this sodium borohydride (1.859 g,49.1 mmol) was added in multiple portions and stirred for 1 h at 0° C.Excess solvent was evaporated and residue was treated with water (100mL), and extracted with ethyl acetate (2×100 mL). The organic layerswere combined dried over anhydrous MgSO₄, filtered and evaporated todryness. The residue was purified by flash column chromatography (silicagel 80 g, eluting with 0-100% ethyl acetate in hexanes) to furnish

-   -   1.        (−)-N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline        (1h) (0.663 g, 8% yield) as an yellow oil as a yellow oil; ¹H        NMR (300 MHz, DMSO-d₆) δ 7.44-7.35 (m, 2H), 7.30-7.21 (m, 2H),        7.19-7.08 (m, 1H), 6.96-6.75 (m, 2H), 6.55 (ddd, J=8.3, 4.6, 2.0        Hz, 1H), 5.26 (td, J=6.0, 2.3 Hz, 1H, D₂O exchangeable), 4.71        (s, 1H), 2.93 (t, J=6.2 Hz, 2H), 2.27 (d, J=7.1 Hz, 3H, 1H, D₂O        exchangeable), 1.09-0.84 (m, 2H), 0.39 (m, 4H), 0.25-0.15 (m,        2H), 0.09-−0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.56;        MS (ES+) 325.4 (M+1); Optical rotation: [α]_(D)=(−) 6.67 [0.27,        methanol]    -   2.        (−)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline        (1i) (4.84 g, 73% yield) as a yellow oil; ¹H NMR (300 MHz,        DMSO-d₆) δ 7.42-7.34 (m, 2H), 7.32-7.23 (m, 2H), 7.22-7.11 (m,        1H), 6.92-6.78 (m, 2H), 6.55 (ddd, J=8.3, 4.5, 2.2 Hz, 1H), 5.04        (s, 2H, D₂O exchangeable), 4.67 (s, 1H), 2.25 (td, J=9.6, 5.3        Hz, 3H; 1H D₂O exchangeable), 1.04-0.80 (m, 1H), 0.50-0.28 (m,        2H), 0.11-0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.92; MS        (ES−) 269.3 (M−1); Optical rotation: [α]_(D)=(−) 12.24 [1.275,        CHCl₃]; Chiral purity checked by performing chiral HPLC using        chiral AD-H column, 1 mL/min, Solvent: 95% Hexane, 5%        isopropanol, UV=260 nM, 25° C. (>99.99 ee).

Step-7: Preparation of 5-(amino(phenyl)methyl)-2-fluoroaniline (1k)

Compound(R)-N-((3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1j) was obtained from the mother liquor from crystallization of mixtureof diastereoisomers of(R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1e) and(R)-N-((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1f). Compound 1k was prepared from(R)-N-((3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1j) (27.8 g, 87 mmol) using procedure reported in step 5 of Scheme 1 tofurnish 5-(amino(phenyl)methyl)-2-fluoroaniline (1k) (14 g, 75%) as alight brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.40-7.32 (m, 2H), 7.27(ddd, J=7.6, 6.7, 1.2 Hz, 2H), 7.21-7.11 (m, 1H), 6.86 (dd, J=11.5, 8.3Hz, 1H), 6.78 (dd, J=9.0, 2.2 Hz, 1H), 6.54 (ddd, J=8.3, 4.5, 2.2 Hz,1H), 5.00 (s, 2H), 4.93 (s, 1H), 2.13 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−138.30; MS (ES) 215.1 (M−1).

Step-8: Preparation ofN-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline(1l) and 5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1m)

Compounds 1l and 1m was prepared from5-(amino(phenyl)methyl)-2-fluoroaniline (1k) (1.081 g, 5.00 mmol)according to procedure reported in step 6 of Scheme 1 to furnish

-   -   1.        N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline        (1l) (0.194 g, 0.598 mmol, 11.96% yield) as a colorless oil; ¹H        NMR (300 MHz, DMSO-d₆) δ 7.44-7.35 (m, 2H), 7.30-7.21 (m, 2H),        7.19-7.11 (m, 1H), 6.94-6.79 (m, 2H), 6.56 (ddd, J=8.2, 4.6, 2.1        Hz, 1H), 5.29 (td, J=5.9, 2.3 Hz, 1H), 4.72 (s, 1H), 2.94 (t,        J=6.2 Hz, 2H), 2.38-2.20 (m, 3H), 1.10-0.97 (m, 1H), 0.91 (m,        1H), 0.40 (m, 4H), 0.21 (m, 2H), 0.03 (m, 2H); ¹⁹F NMR (282 MHz,        DMSO) δ −137.78; MS (ES+) 325.3 (M+1); (ES−) 323.2 (M−1).    -   2. 5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline        (1m) (0.795 g, 2.94 mmol, 58.8% yield) as a colorless oil; ¹H        NMR (300 MHz, DMSO-d₆) δ 7.40-7.33 (m, 2H), 7.27 (tt, J=6.6, 0.9        Hz, 2H), 7.20-7.12 (m, 1H), 6.90-6.78 (m, 2H), 6.54 (ddd, J=8.3,        4.5, 2.1 Hz, 1H), 5.04 (s, 2H), 4.67 (s, 1H), 2.34-2.22 (m, 3H),        0.91 (m, 1H), 0.44-0.30 (m, 2H), 0.09-0.00 (m, 2H); ¹⁹F NMR (282        MHz, DMSO) δ −137.95; MS (ES+) 271.2 (M+1).

Step-9: Preparation of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1o)

To a stirred solution of Cis-hydroxy-D-proline (1 g, 7.63 mmol) inaqueous sodium bicarbonate (61.0 mL, 30.5 mmol, 0.5 molar) was added4-chlorophenyl isocyanate (1n) (1.952 mL, 15.25 mmol) and heated at 80°C. for 5 h. The reaction was cooled to room temperature and solidobtained was filtered. The aqueous filtrate was washed with ethylacetate, adjusted pH to 1 using conc. HCl and extracted with ethylacetate (3×150 mL). The final extracted organic layers were combinedwashed with brine, dried and concentrated in vacuum to afford(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (10) (1.92 g, 6.74 mmol, 88% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 12.33 (s, 1H), 8.41 (s, 1H), 7.61-7.48 (m, 2H),7.32-7.22 (m, 2H), 5.16 (bs, 1H), 4.32 (m, 2H), 3.65 (dd, J=10.2, 5.7Hz, 1H), 3.31 (m, 1H), 2.32 (m, 1H), 1.90 (m, 1H); MS (ES+) 285.2 (M+1),307.2 (M+Na), (ES−) 283.2 (M−1); Optical rotation: [α]_(D)=(+) 48.89[0.27, MeOH].

Step-10: Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(1p)

To a mixture of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1o) (0.2 g, 0.703 mmol),5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1m) (0.19 g,0.703 mmol) in tetrahydrofuran (5 mL) was added ethyl2-ethoxyquinoline-1(2H)-carboxylate (EEDQ, 0.174 g, 0.703 mmol) andstirred at room temperature overnight. The crude reaction mixture wasconcentrated in vacuum and the residue was purified by flash columnchromatography (silica gel 24 g, eluting with 0-100% CMA 80 inchloroform) to afford(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(1p) (65 mg, 0.121 mmol, 17.23% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.65-9.53 (m, 1H), 8.49 (s, 1H), 8.05 (d, J=7.5 Hz, 1H),7.57-7.52 (m, 2H), 7.41-7.35 (m, 2H), 7.27 (dt, J=7.6, 3.2 Hz, 4H),7.20-7.12 (m, 3H), 5.29 (d, J=4.7 Hz, 1H), 4.81 (s, 1H), 4.51 (dd,J=9.0, 4.6 Hz, 1H), 4.34 (q, J=4.8 Hz, 1H), 3.69 (dd, J=10.2, 5.6 Hz,1H), 3.48 (dd, J=10.0, 3.9 Hz, 1H), 2.38 (ddd, J=18.8, 9.2, 4.7 Hz, 2H),2.27 (d, J=6.6 Hz, 2H), 1.96-1.85 (m, 1H), 0.98-0.85 (m, 1H), 0.36 (dt,J=8.4, 2.8 Hz, 2H), 0.05 (dd, J=5.6, 4.0 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −128.72 (d, J=2.9 Hz); MS (ES−) 535.4, 536.3, 537.4 (M, M−1,M−2); HPLC purity 93.5%.

Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(2a)

To a solution of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1o) (0.2 g, 0.703 mmol), 2-fluoroaniline (0.078 g, 0.703 mmol) intetrahydrofuran (5 mL) was added ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.174 g, 0.703 mmol) and stirred atroom temperature overnight. The reaction mixture was concentrated invacuum and the residue obtained was purified by flash columnchromatography (silica gel 24 g, eluting with ethyl acetate in hexanes 0to 100%) to afford(2R,4R)-N1-(4-chlorophenyl)-N2-(2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(2a) (140 mg, 0.371 mmol, 52.7% yield) as a colorless solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.94 (s, 1H), 8.42 (m, 1H), 8.00 (m, 2H),7.78-7.65 (m, 3H), 7.59 (m, 2H), 5.76 (d, J=4.4 Hz, 1H), 5.10-4.92 (m,1H), 4.81 (m, 1H), 4.20-4.08 (m, 1H), 3.98 (m, 1H), 2.92-2.77 (m, 1H),2.47-2.24 (m, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −126.05; MS (ES+) 400.3(M+Na), 777.4 (2M+Na), (ES−) 376.3 (M−1); HPLC purity 99.51%.

Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((+)-(cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (3a)

To a mixture of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1o) (0.205 g, 0.721 mmol),(−)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (1i)(0.195 g, 0.721 mmol) in tetrahydrofuran (5 mL) was added ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.178 g, 0.721 mmol) and stirred atroom temperature overnight. The crude reaction mixture was concentratedin vacuum and the residue obtained was purified by flash columnchromatography (silica gel 24 g, eluting with CMA 80 in chloroformafforded 0 to 100%) to afford(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((+)-(cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide (3a) (25mg, 0.047 mmol, 6.45% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 9.61 (s, 1H), 8.50 (s, 1H), 8.14-7.98 (m, 1H), 7.59-7.51 (m, 2H), 7.38(m, 2H), 7.32-7.23 (m, 4H), 7.21-7.09 (m, 3H), 5.30 (d, J=4.8 Hz, 1H),4.80 (s, 1H), 4.51 (dd, J=9.0, 4.7 Hz, 1H), 4.34 (q, J=4.8 Hz, 1H), 3.69(dd, J=10.0, 5.2 Hz, 1H), 3.48 (dd, J=10.0, 4.1 Hz, 1H), 2.39 (m, 2H),2.27 (d, J=6.7 Hz, 2H), 1.90 (m, 1H), 0.90 (m, 1H), 0.43-0.30 (m, 2H),0.06-0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d6) δ −128.88; Mass spec (ES+)537.4, 539.5 (M,M+2), (ES−) 537.3, 535.4 (M, M−2); HPLC purity 96.99%;Optical rotation: [α]_(D)=(+) 132 [0.2, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(4g) Step: 1 Preparation of 3-(3-cyclopropylacryloyl)benzonitrile (4b)

To a stirred solution of 3-acetylbenzonitrile (4a) (50 g, 344 mmol) inmethanol (800 mL) at 0° C. was added cyclopropanecarboxaldehyde (41 mL,549 mmol) followed by potassium hydroxide (1M aqueous solution, 67 mL,67 mmol). The reaction mixture allowed to attain room temperature andstirred for 14 h. The reaction was acidified with HCl to pH-6 (75 mL,1N) and concentrated in vacuum maintaining bath temperature below 35° C.The residue was diluted with ethyl acetate (1200 mL) and washed withwater (800 mL). The aqueous layer was extracted with ethyl acetate (800mL) and organic layers were combined washed with brine, dried, filteredand concentrated in vacuum to afford3-(3-cyclopropylacryloyl)benzonitrile (4b) (72.42 gm) crude as acolorless liquid, which was used as such in next step; ¹H NMR (300 MHz,DMSO-d₆) δ 8.19 (dp, J=7.8, 1.6 Hz, 1H), 8.11 (dddt, J=6.3, 3.7, 2.6,1.4 Hz, 1H), 7.80-7.65 (m, 2H), 7.32 (dd, J=15.1, 7.6 Hz, 1H), 6.60(ddd, J=15.0, 11.3, 10.4 Hz, 1H), 1.91-1.74 (m, 1H), 1.04 (m, 2H),0.85-0.75 (m, 2H).

Step 2: Preparation of 3-(3-cyclopropylpropanoyl)benzonitrile (4c)

To a stirred solution of 3-(3-cyclopropylacryloyl)benzonitrile (4b)(65.7 g, 333 mmol) in benzene (750 mL) was added tri-n-butyltin hydride(185 mL, 666 mmol) and heated at reflux for 14 h. The reaction mixturewas cooled to room temperature and concentrated in vacuum. The residuewas purified by flash column chromatography (silica gel eluting withethyl acetate in hexanes 0 to 100%) to afford3-(3-cyclopropylpropanoyl)benzonitrile (4c) (23.3, 116.9 mmol, 34%yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (td, J=1.8,0.6 Hz, 1H), 8.24 (ddd, J=7.9, 1.8, 1.2 Hz, 1H), 8.09 (dt, J=7.7, 1.4Hz, 1H), 7.73 (td, J=7.8, 0.6 Hz, 1H), 3.15 (t, J=7.2 Hz, 2H), 1.52 (q,J=7.1 Hz, 2H), 0.81-0.64 (m, 1H), 0.46-0.26 (m, 2H), 0.13-0.00 (m, 2H);MS (ES−) 198.2 (M−1).

Step-3: Preparation of(−)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(4d)

Compound (4d) was prepared from 3-(3-cyclopropylpropanoyl)benzonitrile(4c) (22.8 g, 114 mmol) and (R)-2-methylpropane-2-sulfinamide (13.95 g,114 mmol), using procedure as reported in step 3 of Scheme 1 to afford(−)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(4d) (21.8 g, 72.1 mmol, 63% yield) as a light yellow syrup;

¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (s, 1H), 8.21-8.12 (m, 1H), 8.01 (d,J=7.7 Hz, 1H), 7.70 (t, J=7.9 Hz, 1H), 3.54-3.13 (m, 2H), 1.44 (q, J=7.5Hz, 2H), 1.23 (s, 9H), 0.82-0.65 (m, 1H), 0.44-0.29 (m, 2H), 0.11-0.00(m, 2H); MS (ES+) 303.3 (M+1); (ES−) 301.3 (M−1); Optical rotation:[α]_(D) (−) 66.92 (0.26, MeOH).

Step-4: Preparation of(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e)

To a stirred solution of(−)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(4d) (17.72 g, 58.6 mmol) in toluene (350 mL) at −20° C. was addeddropwise a freshly prepared solution of(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c) (160mL, 120 mmol, 0.75N) over a period of 30 mins. The reaction mixture wasstirred at −20° C. for 1 h and quenched with 1N aqueous KHSO₄ (275 mL).The reaction mixture was stirred for 1 h at room temperature, dilutedwith water (100 mL) basified with 2N NaOH to pH 8 and extracted withethyl acetate (600 mL, 300 mL). The organic layers were combined washedwith water (2×300 mL), brine (300 mL), dried and concentrated in vacuumto dryness. The crude residue was triturated with ethyl acetate andsolid obtained was collected by filtration to obtain on drying undervacuum(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (10.4 g, 42.91% yield) as a white solid. The filtrate wasconcentrated in vacuum and purified by flash column chromatography(silica gel, eluting with ethyl acetate in hexanes 0 to 50%) to(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (4.11 g, 16.95% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 7.78 (t, J=1.6 Hz, 1H), 7.70 (dt, J=7.5, 1.4 Hz, 1H), 7.62 (dt, J=8.1,1.5 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 6.90 (dd, J=11.3, 8.5 Hz, 1H), 6.72(dd, J=8.7, 2.4 Hz, 1H), 6.47 (ddd, J=8.5, 4.3, 2.4 Hz, 1H), 5.27 (s,1H), 5.10 (s, 2H), 2.66-2.40 (m, 2H), 1.20-1.03 (m, 1H), 1.12 (s, 9H),1.01-0.81 (m, 1H), 0.72-0.57 (m, 1H), 0.36 (m, 2H), 0.03-0.15 (m, 2H);19F NMR (282 MHz, DMSO-d₆) δ −137.34; MS (ES+): 436.4 (M+Na); IR (KBr)2235 cm¹; Optical rotation: [α]_(D) (−) 107.95 (0.78, MeOH); Analysiscalculated for C₂₃H₂₈FN₃OS: C, 66.80; H, 6.82; N, 10.16. Found: C,67.06; H, 6.82; N, 10.28.

Step-5: Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(4f)

To a mixture of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1o) (0.2 g, 0.703 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (0.291 g, 0.703 mmol) in tetrahydrofuran (5 mL) was added ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.174 g, 0.703 mmol) and heated atreflux for 16 h. The reaction mixture was concentrated in vacuum andresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with CMA 80 in chloroform afforded 0 to 100%) to afford(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(4f) (175 mg, 0.257 mmol, 36.6% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.66 (s, 1H), 8.52 (s, 1H), 8.07 (m, 1H), 7.79 (m, 1H),7.71 (m, 1H), 7.61-7.47 (m, 4H), 7.31-7.24 (m, 2H), 7.19 (m, 1H), 7.08(m, 1H), 5.50 (s, 1H), 5.33 (d, J=4.7 Hz, 1H), 4.51 (dd, J=9.0, 4.7 Hz,1H), 4.34 (d, J=5.4 Hz, 1H), 3.68 (dd, J=10.0, 5.2 Hz, 1H), 3.49 (dd,J=10.0, 3.9 Hz, 1H), 2.78-2.53 (m, 2H), 2.38 (s, 1H), 1.90 (m, 1H), 1.13(s, 10H), 0.90 (m, 1H), 0.63 (m, 1H), 0.34 (m, 2H), −0.03-−0.19 (m, 2H);⁹F NMR (282 MHz, DMSO-d₆) δ −128.58; MS (ES+) 680.5 (M+1), 702.5, 704.5(M+Cl), (ES−) 714.4, 716.5 (M+Cl); IR (KBr) 2231 cm-1; Optical rotation:[α]_(D)=(−) 19.4 [0.175, MeOH].

Step 6: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(4g)

To a stirred solution of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(4f) (160 mg, 0.235 mmol) in Ethanol (10 mL) was added conc. HCl (0.098mL, 1.176 mmol) and heated at reflux for 1 h. The reaction wasconcentrated in vacuum and residue obtained was purified by flash columnchromatography (silica gel 12 g, eluting with 0-100% CMA 80 inchloroform) to afford(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(4g) (42 mg, 0.073 mmol, 31.0% yield) as a colorless solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.61 (d, J=1.6 Hz, 1H), 8.50 (s, 1H), 8.08-7.99 (m, 1H),7.86 (m, 1H), 7.63 (m, 2H), 7.59-7.51 (m, 2H), 7.46 (m, 1H), 7.32-7.23(m, 2H), 7.12 (m, 2H), 5.30 (d, J=4.8 Hz, 1H), 4.50 (dd, J=9.1, 4.7 Hz,1H), 4.34 (q, J=4.8 Hz, 1H), 3.68 (dd, J=10.1, 5.3 Hz, 1H), 3.48 (dd,J=10.1, 4.0 Hz, 1H), 2.46-2.28 (m, 3H), 2.27-2.16 (m, 2H), 1.90 (m, 1H),1.02 (m, 2H), 0.70-0.56 (m, 1H), 0.34 (m, 2H), −0.08 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −129.29; MS (ES−) 575.3 (M−1); HPLC purity 94.3%;Analysis calculated for C₃₁H₃₁ClFN₅O₃.0.5H₂O: C, 63.64; H, 5.51; N,11.97. Found: C, 63.68; H, 5.75; N, 11.77; Optical rotation: [α]_(D)=(+)93.53 [0.34, MeOH].

Preparation of (2S,4R)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(5e) Step-1: Preparation of (2S,4R)-benzyl1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylate (5b)

Diisopropylethylamine (1.918 mL, 10.98 mmol) was dropped to a suspensionof (2S,4R)-benzyl 4-hydroxypyrrolidine-2-carboxylate4-methylbenzenesulfonate (5a) (4.32 g, 10.98 mmol) in anhydrousDichloromethane (100 mL) stirred at room temperature for 10 minsfollowed by the addition of 1-chloro-4-isocyanatobenzene (1n) (1.686 g,10.98 mmol). The reaction mixture was stirred at room temperature for 2h and poured into water (50 mL). The solid separated was collected byfiltration to furnish (2S,4R)-benzyl1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylate (5b) as awhite solid. The filtrate was extracted with dichloromethane (3×50 mL),the organic layers was combined, washed with brine (50 mL), dried overanhydrous magnesium sulphate, filtered and concentrated in vacuum. Theresidue was combined with filtered solid to obtain (2S,4R)-benzyl1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylate (5b) (4.7g, 12.54 mmol) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (s,1H), 7.61-7.45 (m, 2H), 7.37-7.31 (m, 5H), 7.31-7.25 (m, 2H), 5.21 (d,J=4.0 Hz, 1H), 5.19-5.06 (m, 2H), 4.47 (t, J=7.8 Hz, 1H), 4.37 (m, 1H),3.63 (dd, J=10.5, 4.6 Hz, 1H), 3.49-3.39 (m, 1H), 2.15 (m, 1H), 1.94 (m,1H); MS (ES+) 375.4 (M+1), 397.4 (M+Na), 749.6 (2M+1), 771.6 (2M+Na),(ES−) 373.3 (M−1), 419.3 (M+Cl); Optical rotation: [α]_(D)=(−) 70.08[0.625, MeOH].

Step-2: Preparation of(4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid(5c)

To a stirred solution of (2S,4R)-benzyl1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylate (5b) (3g, 8.00 mmol) in methanol (30 mL) was added at room temperature sodiumhydroxide (1.601 g, 40.0 mmol) and stirred for 2 h. The reaction wasconcentrated in vacuum to remove methanol. The residue was dissolved inwater (10 mL) and washed with ethyl acetate (2×20 mL). The aqueous layerwas acidified with conc HCl to pH 2, extracted with ethyl acetate (3×75mL). The organic layers were combined washed with water (2×50 mL), brine(50 mL), dried, filtered and concentrated in vacuum to afford(4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid(5c) (1 g, 3.51 mmol, 43.9% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.21 (s, 1H), 8.45 (2s, 1H), 7.61-7.42 (m, 2H), 7.37-7.21(m, 2H), 5.17 (d, J=3.9 Hz, 1H), 4.32 (m, 2H), 3.63 (m, 1H), 3.34-3.21(m, 1H), 2.31 (m, 1H), 2.22-2.00 (m, 1H); MS (ES+) 285.2 (M+1), 307.1(M+Na), (ES−) 283.1 (M−1).

Step-3: Preparation of(2S,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(5d) and(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(4f)

Reaction of(4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid(5c) (550 mg, 1.932 mmol) with(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (799 mg, 1.932 mmol) in tetrahydrofuran (5 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (478 mg, 1.932 mmol) as reported instep 5 of Scheme 4 gave after purification by flash columnchromatography (silica gel 24 g, eluting with CMA 80 in chloroformafforded 0 to 100%)

-   -   1.        (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide        (4f) (267 mg, 0.393 mmol, 20.32% yield) as a white solid,        followed by.    -   2.        (2S,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide        (5d) (203 mg, 0.298 mmol, 15.45% yield) as a light orange solid;        ¹H NMR (300 MHz, DMSO-d₆) δ 9.84 (s, 1H), 8.48 (s, 1H), 7.94 (d,        J=7.4 Hz, 1H), 7.77 (d, J=1.9 Hz, 1H), 7.70 (dt, J=7.3, 1.5 Hz,        1H), 7.52 (m, 4H), 7.31-7.23 (m, 2H), 7.19 (m, 1H), 7.09 (m,        1H), 5.49 (s, 1H), 5.18 (d, J=3.7 Hz, 1H), 4.66 (t, J=7.5 Hz,        1H), 4.39 (s, 1H), 3.67 (m, 1H), 3.47-3.37 (m, 1H), 2.68-2.54        (m, 2H), 2.17-2.05 (m, 1H), 2.06-1.87 (m, 1H), 1.11 (s, 10H),        0.89 (m, 1H), 0.72-0.49 (m, 1H), 0.33 (m, 2H), −0.02-−0.20 (m,        2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.00; MS (ES−) 678.4, 679.5        (M−1); Optical rotation [α]_(D)=(−) 190 [0.08, MeOH].

Step-4: Preparation of(2S,4R)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(5e)

Reaction of (2S,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(5d) (183 mg, 0.269 mmol) in ethanol (5 mL) using Conc. HCl (0.224 mL,2.69 mmol) as reported in Scheme 4 step 6 gave after purification byflash column chromatography (silica gel, 12 g eluting with 0 to 30% CMA80 in chloroform)(2S,4R)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(5e) (100 mg, 0.174 mmol, 64.5% yield) as a colorless solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.77 (s, 1H), 8.47 (s, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.86(t, J=1.7 Hz, 1H), 7.66-7.58 (m, 2H), 7.57-7.51 (m, 2H), 7.45 (t, J=7.8Hz, 1H), 7.31-7.24 (m, 2H), 7.15-7.08 (m, 2H), 5.17 (d, J=3.8 Hz, 1H),4.65 (t, J=7.5 Hz, 1H), 4.40 (s, 1H), 3.67 (dd, J=10.3, 4.6 Hz, 1H),3.43 (m, 1H), 2.30 (m, 2H), 2.25-2.07 (m, 3H), 2.03-1.89 (m, 1H),1.09-0.93 (m, 2H), 0.62 (m, 1H), 0.38-0.28 (m, 2H), −0.04-−0.14 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.76; MS (ES+) 598.4, 600.4 (M+Na);HPLC: 5.12 min. (93.86%); Optical rotation [α]_(D)=(−) 96.05 [0.86,MeOH].

Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide(6c) and(2S,4R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide(6d) Step-1: Preparation of (4R)-methyl1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylate(6a)

To a stirred solution of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1o) (0.837 g, 2.94 mmol) in N,N-Dimethylformamide (20 mL) at 0° C.was added sodium hydride (60% dispersion in mineral oil, 0.941 g, 23.52mmol) and stirred at 0° C. for 1 h. To the reaction mixture was added at0° C. methyl iodide (1.471 mL, 23.52 mmol) and stirred for 2 h. Thereaction was quenched by adding 1N aqueous KHSO₄ (15 mL), water (100 mL)and extracted with ethyl acetate (3×100 mL). The organic layers werecombined washed with water (2×50 mL), brine (50 mL), dried, filtered andconcentrated in vacuum. The crude residue was purified by flash columnchromatography [silica gel 40 g, eluting with a (9:1) ethyl acetate andmethanol in hexanes 0 to 40%] to afford ((4R)-methyl1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylate(6a) (250 mg, 0.765 mmol, 26.0% yield) was used in the next reaction; ¹HNMR (300 MHz, DMSO-d₆) δ 7.49-7.40 (m, 2H), 7.37-7.30 (m, 2H), 4.54-4.30(m, 1H), 3.90-3.74 (m, 1H), 3.67 (d, J=4.7 Hz, 3H), 3.29-3.18 (m, 1H),3.11 (2s, 3H), 3.06 (2s, 3H), 2.70-2.21 (m, 2H), 1.80-1.60 (m, 1H); MS(ES+) 349.3 (M+1).

Step-2: Preparation of((4R)-1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylicacid (6b)

To a stirred solution of (4R)-methyl1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylate(6a) (250 mg, 0.765 mmol) in methanol (10 mL) was added at roomtemperature sodium hydroxide (0.765 mL, 3.06 mmol, 4N aqueous), stirredat room temperature overnight and concentrated in vacuum to removemethanol. The residue was dissolved in water (30 mL), acidified with 1NKHSO₄ and extracted with ethyl acetate (3×50 mL). The organic layerswere combined washed with water (20 mL), brine (20 mL), dried, filteredand concentrated in vacuum to afford((4R)-1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylicacid (6b) (230 mg, 0.735 mmol, 96% yield) as white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.64 (s, 1H), 7.47-7.31 (m, 4H), 4.40-4.24 (m, 1H),3.90-3.73 (m, 1H), 3.33-3.16 (m, 1H), 3.11 (2s, 3H), 3.08 (2s, 3H),2.50-2.19 (m, 2H), 1.80-1.57 (m, 1H); MS (ES+) 313.3, (ES−) 311.2 (M−1).

Step-3: Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide(6c) and(2S,4R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide(6d)

To a mixture of((4R)-1-((4-chlorophenyl)(methyl)carbamoyl)-4-methoxypyrrolidine-2-carboxylicacid (6b) (230 mg, 0.735 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (304 mg, 0.735 mmol) in tetrahydrofuran (5 mL) was added ethyl2-ethoxyquinoline-1(2H)-carboxylate (EEDQ, 182 mg, 0.735 mmol) andheated at reflux for 16 h. The reaction mixture was concentrated invacuum and the residue obtained was purified by flash columnchromatography (silica gel 40 g, eluting with CMA 80 in chloroform, 0 to100%) to obtain:

-   -   1.        (2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide        (6c) (279 mg, 0.394 mmol, 53.6% yield) as a white solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 9.89 (s, 1H), 8.02 (d, J=7.1 Hz, 1H), 7.80        (d, J=1.8 Hz, 1H), 7.73 (dt, J=7.4, 1.3 Hz, 1H), 7.66-7.58 (m,        1H), 7.54 (d, J=7.7 Hz, 1H), 7.40 (s, 4H), 7.21 (dd, J=10.5, 8.8        Hz, 1H), 7.17-7.05 (m, 1H), 5.55 (s, 1H), 4.75-4.56 (m, 1H),        3.80 (s, 1H), 3.16 (s, 3H), 3.09 (s, 3H), 3.03 (d, J=11.2 Hz,        1H), 2.78-2.67 (m, 2H), 2.66-2.54 (m, 1H), 2.47-2.23 (m, 1H),        1.82-1.61 (m, 1H), 1.15 (d, J=1.4 Hz, 9H), 1.14-1.00 (m, 1H),        1.04-0.76 (m, 1H), 0.66 (m, 1H), 0.36 (m, 2H), 0.08-−0.11 (m,        2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −126.84; MS (ES+) 708.6 (M+1),        730.6, 732.6 (M+Cl), (ES−) 706.6, 708.6 (M−1).    -   2.        (2S,4R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide        (6d) (200 mg, 0.282 mmol, 38.4% yield) as a white solid: ¹H NMR        (300 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.95 (d, J=7.3 Hz, 1H), 7.81        (t, J=1.7 Hz, 1H), 7.72 (dt, J=7.4, 1.3 Hz, 1H), 7.62 (d, J=8.3        Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.40 (s, 4H), 7.22 (dd, J=10.4,        8.7 Hz, 1H), 7.14 (m, 1H), 5.56 (s, 1H), 4.58 (t, J=8.4 Hz, 1H),        3.94-3.79 (m, 1H), 3.29 (m, 1H), 3.10 (s, 3H), 3.08 (s, 3H),        2.73 (m, 2H), 2.57 (m, 1H), 2.43 (m, 1H), 1.74-1.50 (m, 1H),        1.28-1.16 (m, 1H), 1.15 (2s, 9H), 0.99-0.78 (m, 1H), 0.66 (m,        1H), 0.37 (m, 2H), 0.10-−0.11 (m, 2H); ¹⁹F NMR (282 MHz,        DMSO-d6) δ −127.21; MS (ES+) 708.6 (M+1), 730.6, 732.6 (M+Cl),        (ES−) 706.6, 708.6 (M−1).

Preparation of(2R,4R)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide(6e)

Reaction of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide(6c) (170 mg, 0.240 mmol) in ethanol (5 mL) using conc. HCl (0.200 mL,2.400 mmol) as reported in Scheme 4 step 6 for preparation of compound4g gave after purification by flash column chromatography (silica gel,12 g eluting with 0 to 30% CMA 80 in chloroform)(2R,4R)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide(6e) (115 mg, 0.190 mmol, 79% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.65 (s, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.89 (t, J=1.7 Hz, 1H),7.66 (ddt, J=10.3, 7.7, 1.4 Hz, 2H), 7.49 (d, J=7.9 Hz, 1H), 7.46-7.34(m, 4H), 7.19-7.12 (m, 2H), 4.56 (t, J=8.3 Hz, 1H), 3.93-3.77 (m, 1H),3.10 (s, 3H), 3.08 (s, 3H), 2.61-2.39 (m, 2H), 2.36 (s, 2H), 2.31-2.14(m, 2H), 1.72-1.52 (m, 1H), 1.13-0.97 (m, 2H), 0.77-0.57 (m, 1H),0.42-0.27 (m, 2H), 3.42-3.19 (m, 1H), −0.00-−0.07 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −128.01; MS (ES+) 626.4, 628.4 (M+Na); HPLC purity99.04%; Optical rotation [α]_(D)=(−) 142.49 [1.005, MeOH].

Preparation of(2S,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide(6f)

Reaction of(2S,4R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide(6d) (238 mg, 0.336 mmol) in ethanol (5 mL) using conc. HCl (0.280 mL,3.36 mmol) as reported in Scheme 4 step 6 for preparation of compound 4ggave after purification by flash column chromatography (silica gel, 12 geluting with 0 to 30% CMA 80 in chloroform)(2S,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-N1-methylpyrrolidine-1,2-dicarboxamide(6f) (106 mg, 0.175 mmol, 52.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.81 (s, 1H), 7.98-7.91 (m, 1H), 7.89 (t, J=1.7 Hz, 1H),7.70-7.62 (m, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.40 (d, J=1.5 Hz, 4H),7.18-7.10 (m, 2H), 4.63 (dd, J=10.3, 7.0 Hz, 1H), 3.80 (t, J=3.5 Hz,1H), 3.15 (s, 3H), 3.09 (s, 3H), 3.02 (m, 1H), 2.73 (m, 1H), 2.35 (s,3H), 2.24 (m, 2H), 1.70 (m, 1H), 1.05 (m, 2H), 0.66 (m, 1H), 0.36 (m,2H), −0.03 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.42; MS (ES+)626.4, 627.5 (M+Na), (ES−) 602.5, 603.3 (M−1); HPLC purity 91.30%;Optical rotation [α]_(D)=(+) 189.77 [0.86, MeOH.

Preparation of(R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(7c) Step-1: Preparation of(R)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid (7a)

Reaction of D-Proline (1.0 g, 8.69 mmol) in aqueous sodium bicarbonate(69.5 mL, 34.7 mmol, 0.5M) with 4-chlorophenyl isocyanate (1n) (2.223mL, 17.37 mmol) using the reaction and workup conditions as reported instep 9 of Scheme 1 gave(R)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid (7a) (1.6g, 5.95 mmol, 68.6% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ12.45 (s, 1H), 8.42 (s, 1H), 7.66-7.41 (m, 2H), 7.41-7.09 (m, 2H),4.44-4.16 (m, 1H), 3.67-3.38 (m, 2H), 2.28-2.05 (m, 1H), 1.92 (m, 3H);MS (ES+) 269.1 (M+1), 291.2, 293.2 (M+Na), (ES−) 267.2, 269.1 (M−1);Optical rotation [α]_(D)=(+) 59.33 [0.3, MeOH].

Step-2: Preparation of(R)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(7b)

Reaction of (R)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid(7a) (0.5 g, 1.861 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (0.770 g, 1.861 mmol) in tetrahydrofuran (25 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.460 g, 1.861 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%)(R)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(7b) (1.08 g, 1.626 mmol, 87% yield) as colorless solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.84 (s, 1H), 8.45 (s, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.78(d, J=1.8 Hz, 1H), 7.71 (dt, J=7.3, 1.4 Hz, 1H), 7.65-7.44 (m, 4H),7.32-7.24 (m, 2H), 7.19 (dd, J=10.4, 8.7 Hz, 1H), 7.16-7.03 (m, 1H),5.53 (s, 1H), 4.68-4.45 (m, 1H), 3.71-3.55 (m, 2H), 3.56-3.42 (m, 1H),2.77-2.55 (m, 1H), 2.22-2.04 (m, 1H), 1.95 (m, 4H), 1.12 (s, 9H),1.00-0.75 (m, 1H), 0.74-0.50 (m, 1H), 0.41-0.26 (m, 2H), 0.10-−0.25 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.07; MS (ES+) 686.5, 688.5 (M+Na);Optical rotation [α]_(D)=(+) 142.65 [0.415, MeOH].

Step 3:(R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(7c)

Reaction of(R)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(7b) (0.9 g, 1.355 mmol) in ethanol (20 mL) using conc. HCl (1.129 mL,13.55 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel 25 g, eluting with CMA 80 inchloroform 0 to 30%)(R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(7c) (200 mg, 0.357 mmol, 26.4% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.76 (s, 1H), 8.43 (s, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.86(t, J=1.6 Hz, 1H), 7.63 (ddt, J=7.8, 6.1, 1.3 Hz, 2H), 7.59-7.51 (m,2H), 7.46 (t, J=7.8 Hz, 1H), 7.33-7.23 (m, 2H), 7.19-7.05 (m, 2H),4.64-4.52 (m, 1H), 3.61 (m, 1H), 3.49 (m, 1H), 2.31 (m, 2H), 2.22 (m,2H), 2.14 (m, 1H), 1.96 (m, 3H), 1.04 (m, 2H), 0.63 (m, 1H), 0.33 (m,2H), −0.07 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −127.97; MS (ES+) 582.4(M+Na), (ES−) 558.5 (M−1), 594.3, 596.3 (M+Cl); IR(KBr) 3385, 2229,1657, 1527, 1494, 1406 cm¹; Optical rotation [α]_(D)=(+) 23.57 [0.28,MeOH].

Preparation of(S)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(8c) Step-1: Preparation of(S)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid (8a)

Reaction of L-Proline (1.0 g, 8.69 mmol) in aqueous sodium bicarbonate(69.5 mL, 34.7 mmol, 0.5M) with 4-chlorophenyl isocyanate (1n) (2.223mL, 17.37 mmol) using the reaction and workup conditions as reported instep 9 of Scheme 1 gave(S)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid (8a) (1.643g, 6.11 mmol, 70.4% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ12.45 (s, 1H), 8.42 (s, 1H), 7.60-7.45 (m, 2H), 7.34-7.20 (m, 2H),4.39-4.19 (m, 1H), 3.63-3.39 (m, 1H), 2.17 (m, 1H), 2.02-1.80 (m, 4H);MS (ES+) 269.3 (M+1), 291.3, 293.3 (M+Na); (ES−) 267.2 (M−1); Opticalrotation [α]_(D)=(−) 51.85 [0.27, MeOH].

Step-2: Preparation of(S)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(8b)

Reaction of (S)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid(8a) (0.5 g, 1.861 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (0.770 g, 1.861 mmol) in tetrahydrofuran (25 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.46 g, 1.861 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%)(S)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(8b) (1.002 g, 1.509 mmol, 81% yield) as colorless solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.83 (s, 1H), 8.45 (s, 1H), 8.02-7.91 (m, 1H), 7.78 (d,J=1.8 Hz, 1H), 7.71 (dt, J=7.3, 1.5 Hz, 1H), 7.61-7.45 (m, 4H),7.32-7.25 (m, 2H), 7.20 (dd, J=10.4, 8.7 Hz, 1H), 7.15-7.04 (m, 1H),5.51 (s, 1H), 4.72-4.49 (m, 1H), 3.62 (m, 1H), 3.58-3.42 (m, 1H), 2.62(m, 1H), 2.14 (m, 1H), 2.06-1.85 (m, 4H), 1.12 (s, 10H), 0.97-0.78 (m,1H), 0.70-0.54 (m, 1H), 0.45-0.26 (m, 2H), 0.02-−0.17 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −127.28; MS (ES+) 686.5, 688.5 (M+Na); Opticalrotation [α]_(D)=(−) 208.15 [0.27, MeOH].

Step 3:(S)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(8c)

Reaction of(S)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(8b) (0.9 g, 1.355 mmol) in ethanol (20 mL) using conc. HCl (1.129 mL,13.55 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel 25 g, eluting with CMA 80 inchloroform 0 to 30%)(S)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(8c) (300 mg, 0.536 mmol, 39.5% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.76 (s, 1H), 8.43 (s, 1H), 7.96 (d, J=7.3 Hz, 1H), 7.86(t, J=1.7 Hz, 1H), 7.63 (ddt, J=7.8, 4.7, 1.3 Hz, 2H), 7.59-7.51 (m,2H), 7.46 (t, J=7.8 Hz, 1H), 7.31-7.24 (m, 2H), 7.12 (d, J=9.0 Hz, 2H),4.66-4.45 (m, 1H), 3.69-3.54 (m, 1H), 3.56-3.42 (m, 1H), 2.37-2.28 (m,2H), 2.27-2.06 (m, 2H), 2.04-1.86 (m, 4H), 1.11-0.89 (m, 2H), 0.73-0.54(m, 1H), 0.40-0.25 (m, 2H), −0.02-−0.15 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −128.04; MS (ES+) 582.4; 584.5 (M+Na), (ES−) 558.4 (M−1); IR(KBr) 3386, 2229, 1655, 1594, 1526, 1494, 1405 cm-1; Optical Rotation[α]_(D)=(−)102.42[1.035, MeOH]; Analysis calculated for C₃₁H₃₁ClFN₅O₂;C, 66.48; H, 5.58; N, 12.50. Found: C, 66.23; H, 5.71; N, 12.24.

Preparation of(2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(9c) Step-1: Preparation of (2R,4S)-1-(4-chlorophenylcarbamoyl)-4hydroxypyrrolidine-2-carboxylic acid (9a)

Reaction of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid(trans-D-4-hydroxyproline, 1.0 g, 7.63 mmol) in aqueous sodiumbicarbonate (61.0 mL, 30.5 mmol, 0.5M) with 4-chlorophenyl isocyanate(1n) (1.952 mL, 15.25 mmol) using the reaction and workup conditions asreported in step 9 of Scheme 1 gave(2R,4S)-1-(4-chlorophenylcarbamoyl)-4 hydroxypyrrolidine-2-carboxylicacid (9a) (1.643 g, 5.77 mmol, 76% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.43 (s, 1H), 8.47 (s, 1H), 7.57-7.48 (m, 2H),7.31-7.22 (m, 2H), 5.16 (d, J=3.9 Hz, 1H), 4.34 (m, 2H), 3.60 (dd,J=10.4, 4.6 Hz, 1H), 3.45-3.35 (m, 1H), 2.12 (m, 1H), 1.92 (m, 1H); MS(ES+) 285.3 (M+1), 307.2, 309.3 (M+Na), (ES−) 283.2, 285.3 (M−1);Optical Rotation [α]_(D)=(+)54.375 [0.32, MeOH].

Step-2: Preparation of(2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(9b)

Reaction of (2R,4S)-1-(4-chlorophenylcarbamoyl)-4hydroxypyrrolidine-2-carboxylic acid (9a) (0.7 g, 2.459 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (1.017 g, 2.459 mmol) in tetrahydrofuran (25 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.608 g, 2.459 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%)(2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(9b) (1.37 g, 2.014 mmol, 82% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.86 (s, 1H), 8.49 (s, 1H), 7.91 (dd, J=7.5, 2.4 Hz, 1H),7.78 (t, J=1.7 Hz, 1H), 7.71 (dt, J=7.4, 1.4 Hz, 1H), 7.63-7.45 (m, 4H),7.31-7.23 (m, 2H), 7.19 (dd, J=10.3, 8.7 Hz, 1H), 7.14-7.03 (m, 1H),5.53 (s, 1H), 5.19 (d, J=3.7 Hz, 1H), 4.66 (t, J=7.5 Hz, 1H), 4.39 (m,1H), 3.67 (dd, J=10.4, 4.6 Hz, 1H), 3.44 (d, J=10.0 Hz, 1H), 2.80-2.53(m, 1H), 2.10 (m, 1H), 2.04-1.84 (m, 1H), 1.12 (s, 10H), 1.05 (s, 1H),0.90 (s, 1H), 0.63 (s, 1H), 0.39-0.27 (m, 2H), −0.03-−0.16 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −126.81; MS (ES+) 702.5, 704.5 (M+Na); OpticalRotation [α]_(D)=(+) 20.71 [0.28, MeOH].

Step 3:(2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(9c)

Reaction of(2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(9b) (0.725 g, 1.066 mmol) in ethanol (20 mL) using conc. HCl (0.888 mL,10.66 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel 25 g, eluting with CMA 80 inchloroform 0 to 30%)(2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(9c) (210 mg, 0.365 mmol, 34.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.77 (s, 1H), 8.46 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.86(t, J=1.7 Hz, 1H), 7.63 (m, 2H), 7.59-7.50 (m, 2H), 7.45 (t, J=7.8 Hz,1H), 7.32-7.22 (m, 2H), 7.18-7.08 (m, 2H), 5.17 (d, J=3.8 Hz, 1H), 4.64(t, J=7.5 Hz, 1H), 4.39 (m, 1H), 3.67 (dd, J=10.3, 4.6 Hz, 1H),3.47-3.36 (m, 2H), 2.31 (m, 2H), 2.21 (m, 2H), 2.11 (m, 1H), 1.11-0.91(m, 2H), 0.62 (m, 1H), 0.41-0.22 (m, 2H), −0.08 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −127.52; MS (ES+) 598.4, 600.4 (M+Na), (ES−) 610.4,612.4 (M+Cl); Optical rotation [α]_(D)=(+) 132.69 [0.82, MeOH].

Preparation of(2S,4S)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(10c) Step-1: Preparation of(2S,4S)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (10a)

Reaction of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid(cis-L-4-hydroxyproline, 1.0 g, 7.63 mmol) in aqueous sodium bicarbonate(61.0 mL, 30.5 mmol, 0.5M) with 4-chlorophenyl isocyanate (1n) (1.952mL, 15.25 mmol) using the reaction and workup conditions as reported instep 9 of Scheme 1 gave(2S,4S)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (10a) (1.643 g, 5.77 mmol, 76% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.33 (s, 1H), 8.41 (s, 1H), 7.64-7.43 (m, 2H),7.37-7.14 (m, 2H), 5.09 (s, 1H), 4.51-4.16 (m, 2H), 3.65 (dd, J=10.3,5.6 Hz, 1H), 3.32 (m, 1H), 2.32 (m, 1H), 1.97-1.78 (m, 1H); MS (ES+)307.2, 309.2 (M+Na), (ES−) 283.2, 285.2 (M−1); Optical Rotation[α]_(D)=(−) 37.74 [0.265, MeOH].

Step-2: Preparation of(2S,4S)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(10b)

Reaction of(2S,4S)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (10a) (0.7 g, 2.459 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (1.017 g, 2.459 mmol) in tetrahydrofuran (25 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.608 g, 2.459 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%)(2S,4S)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(10b) (0.961 g, 1.413 mmol, 57.5% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.66 (s, 1H), 8.52 (s, 1H), 8.06 (dd, J=7.6, 2.4 Hz,1H), 7.79 (m, 1H), 7.71 (m, 1H), 7.62-7.45 (m, 4H), 7.34-7.24 (m, 2H),7.20 (dd, J=10.5, 8.7 Hz, 1H), 7.14-7.03 (m, 1H), 5.49 (s, 1H), 5.32 (d,J=4.5 Hz, 1H), 4.51 (dd, J=9.0, 4.7 Hz, 1H), 4.39-4.25 (m, 1H), 3.68(dd, J=10.1, 5.2 Hz, 1H), 3.49 (dd, J=9.9, 3.9 Hz, 1H), 2.75-2.51 (m,2H), 2.49-2.20 (m, 1H), 1.97-1.81 (m, 1H), 1.13 (s, 9H), 1.07 (m, 1H),0.90 (m, 1H), 0.64 (m, 1H), 0.40-0.26 (m, 2H), −0.06 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −128.68; MS (ES+) 702.5, 704.5 (M+Na), (ES−) 678.6,680.5 (M−1); Optical Rotation [α]_(D)=(−) 153.33 [0.27, MeOH].

Step 3: Preparation of(2S,4S)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(10c)

Reaction of(2S,4S)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(10b) (0.5 g, 0.735 mmol) in ethanol (20 mL) using conc. HCl (0.613 mL,7.35 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel 25 g, eluting with CMA 80 inchloroform 0 to 30%)(2S,4S)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(10c) (50 mg, 0.087 mmol, 11.81% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.50 (s, 1H), 8.05 (d, J=7.3 Hz, 1H),7.86 (t, J=1.7 Hz, 1H), 7.63 (m, 2H), 7.59-7.50 (m, 2H), 7.46 (t, J=7.8Hz, 1H), 7.34-7.24 (m, 2H), 7.19-7.04 (m, 2H), 5.30 (d, J=4.9 Hz, 1H),4.51 (dd, J=9.0, 4.7 Hz, 1H), 4.34 (d, J=5.2 Hz, 1H), 3.69 (dd, J=10.1,5.3 Hz, 1H), 3.54-3.43 (m, 1H), 2.40-2.08 (m, 5H), 1.90 (m, 1H), 1.02(m, 2H), 0.63 (m, 1H), 0.34 (m, 2H), −0.07 (s, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −129.13; MS (ES+) 598.4, 600.4 (M+Na); Optical Rotation[α]_(D)=(−) 51.85 [0.7, MeOH]; Analysis calculated forC₃₁H₃₁ClFN₅O₃.0.75H₂O: C, 63.15; H, 5.56; N, 11.88. Found: C, 63.02; H,5.89; N, 10.83.

Preparation of(2S,4S)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(11e) Step-1: Preparation of (2S,4S)-4-methoxypyrrolidine-2-carboxylicacid hydrochloride (11b)

To a stirred solution of(2S,4S)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(11a) (Prepared according to the procedure reported inBenzimidazole-proline derivatives as orexin receptor antagonists andtheir preparation; By Boss, Christoph et al; From PCT Int. Appl.,2013182972, 12 Dec. 2013; 0.25 g, 1.019 mmol) in tetrahydrofuran (10 mL)was added 6N aqueous HCl (0.680 mL, 4.08 mmol) and stirred at roomtemperature overnight. The reaction was concentrated and dried in vacuumto afford (2S,4S)-4-methoxypyrrolidine-2-carboxylic acid hydrochloride(11b) (0.185 g, 1.019 mmol, 100% yield) as a white solid which was usedas such in next step; ¹H NMR (300 MHz, DMSO-d₆/D₂O) δ 4.42 (t, J=6.7 Hz,1H), 4.06 (m, 1H), 3.38 (d, J=12.4 Hz, 1H), 3.25-3.18 (m, 1H), 3.16 (s,3H), 2.30 (dd, J=7.3, 3.2 Hz, 2H).

Step-2: Preparation of(2S,4S)-1-(4-chlorophenylcarbamoyl)-4-methoxypyrrolidine-2-carboxylicacid (11c)

Reaction of (2S,4S)-4-methoxypyrrolidine-2-carboxylic acid hydrochloride(11b) (182 mg, 1.0 mmol) in aqueous sodium bicarbonate (10 mL, 20 mmol,0.5M) with 4-chlorophenyl isocyanate (1n) (10.256 mL, 2.0 mmol) usingthe reaction and workup conditions as reported in step 9 of Scheme 1gave(2S,4S)-1-(4-chlorophenylcarbamoyl)-4-methoxypyrrolidine-2-carboxylicacid (11c) (133 mg, 0.445 mmol, 44.5% yield) MS (ES+) 321.3, 323.3(M+Na), (ES−) 297.3, 299.3 (M−1).

Step-3: Preparation of(2S,4S)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(11d)

Reaction of(2S,4S)-1-(4-chlorophenylcarbamoyl)-4-methoxypyrrolidine-2-carboxylicacid (11c) (120 mg, 0.402 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (166 mg, 0.402 mmol) in tetrahydrofuran (20 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (99 mg, 0.402 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%)(2S,4S)-N1-(4-chlorophenyl)-N2-(5-((1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(11d) (156 mg, 0.225 mmol, 55.9% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.51 (s, 1H), 8.53 (s, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.79(s, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.64-7.46 (m, 4H), 7.35-7.25 (m, 2H),7.24-7.14 (m, 1H), 7.10 (s, 1H), 5.48 (s, 1H), 4.54 (dd, J=9.2, 3.9 Hz,1H), 4.07 (m, 1H), 3.72 (dd, J=10.6, 5.0 Hz, 1H), 3.61 (dd, J=10.0, 2.4Hz, 1H), 3.22 (s, 3H), 2.69-2.51 (m, 2H), 2.43-2.24 (m, 1H), 2.23-2.06(m, 1H), 1.12 (s, 10H), 0.99-0.79 (m, 1H), 0.63 (s, 1H), 0.42-0.27 (m,2H), 0.06-−0.16 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.19; MS (ES+)716.6, 718.5 (M+Na).

Step 4: Preparation of(2S,4S)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(11e)

Reaction of(2S,4S)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(11d) (0.143 g, 0.206 mmol) in ethanol (20 mL) using conc. HCl (0.172mL, 2.060 mmol) as reported in step 6 of Scheme 4 gave afterpurification by flash column chromatography (silica gel 25 g, elutingwith CMA 80 in chloroform 0 to 30%)(2S,4S)-N2-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(11e) (80 mg, 0.136 mmol, 65.8% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.45 (d, J=1.3 Hz, 1H), 8.51 (s, 1H), 7.90 (d, J=7.7 Hz,1H), 7.86 (m, 1H), 7.63 (m, 2H), 7.58-7.52 (m, 2H), 7.46 (t, J=7.8 Hz,1H), 7.32-7.25 (m, 2H), 7.14 (s, 1H), 7.11 (s, 1H), 4.53 (dd, J=9.1, 3.9Hz, 1H), 4.07 (m, 1H), 3.73 (dd, J=10.6, 5.1 Hz, 1H), 3.61 (dd, J=10.4,3.3 Hz, 1H), 3.22 (s, 3H), 2.47-1.98 (m, 6H), 1.11-0.92 (m, 2H), 0.63(m, 1H), 0.33 (m, 2H), −0.07 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.86; MS (ES+) 612.4, 614.4 (M+Na); IR (KBr) 2229 cm⁻¹; Opticalrotation [α]_(D)=(−)56.57 [0.495, MeOH]

Preparation of (R)-benzyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate(12b) Step-1: Preparation of(R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a)

To a stirred solution of D-Proline (1.2 g, 10.42 mmol) in 2N aqueousNaOH solution (20.85 mL, 41.7 mmol) at 0° C. was added benzylchloroformate (1.488 mL, 10.42 mmol) and allowed to warm to roomtemperature overnight. The reaction was washed with MTBE (2×25 mL),acidified with conc HCl and extracted with ethyl acetate (2×200 mL). Theethyl acetate layers were combined washed with water (50 mL), brine (25mL) dried and concentrated in vacuum to afford(R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a) (2.41 g,9.67 mmol, 93% yield) which was used as such in next step; ¹H NMR (300MHz, DMSO-d₆) δ 12.66 (s, 1H), 7.42-7.25 (m, 5H), 5.14-4.97 (m, 2H),4.20 (ddd, J=22.7, 8.8, 3.5 Hz, 1H), 3.50-3.25 (m, 2H), 2.32-2.08 (m,1H), 1.97-1.75 (m, 3H); MS (ES+) 250.2 (M+1), 272.2 (M+Na), (ES−) 248.2(M−1), 284.2 (M+Cl), 497.4 (2M−1).

Step-2: Preparation of (R)-benzyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate(12b)

Reaction of (R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a)(1 g, 4.01 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (1.659 g, 4.01 mmol) in tetrahydrofuran (50 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.992 g, 4.01 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%) (R)-benzyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-,1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate(12b) (2.4 g, 3.72 mmol, 93% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.86 (d, J=11.1 Hz, 1H), 7.92 (t, J=9.0 Hz, 1H), 7.78 (d,J=1.7 Hz, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.65-7.56 (m, 1H), 7.51 (m, 1H),7.37 (m, 2H), 7.29-7.06 (m, 5H), 5.52 (d, J=10.5 Hz, 1H), 5.14-4.93 (m,2H), 4.62-4.38 (m, 1H), 3.58-3.33 (m, 2H), 2.72-2.57 (m, 1H), 2.33-2.08(m, 1H), 1.97-1.73 (m, 4H), 1.12 (2s, 9H for rotamers), 1.11-1.00 (m,1H), 0.86 (m, 1H), 0.62 (m, 1H), 0.34 (m, 2H), 0.01-−0.18 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −126.74; MS (ES+) 645.6 (M+1), 667.6 (M+Na),(ES−) 643.6 (M−1); Optical rotation [α]_(D)=(−) 21.18 [0.255, MeOH].

Preparation of(R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)pyrrolidine-1,2-dicarboxamide(13e) Step 1: Preparation of phenyl 5-chloropyridin-2-ylcarbamate (13b)

To an ice-water bath cooled solution of 2-amino-5-chloropyridine (13a)(5 g, 38.9 mmol) in dichloromethane (100 mL) was added pyridine (4.72mL, 58.3 mmol) and phenyl chloroformate (4.88 mL, 38.9 mmol). Theresulting mixture was stirred in ice-water bath for 2 h, diluted withwater (100 mL) and dichloromethane (50 mL). The solid obtained wascollected by filtration dried at 50° C. under vacuum to give phenyl5-chloropyridin-2-ylcarbamate (13b) (9.519 g, 38.3 mmol, 98% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.38 (dd, J=2.6,0.8 Hz, 1H), 7.93 (dd, J=9.0, 2.6 Hz, 1H), 7.84 (dd, J=8.9, 0.8 Hz, 1H),7.51-7.37 (m, 2H), 7.36-7.17 (m, 3H).

Step 2: Preparation of(R)-N-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-2-carboxamide(13c)

To a suspension of palladium on carbon 10% (0.165 g, 0.155 mmol) inethanol (75 mL) was added a solution of (R)-benzyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate(12b) (1 g, 1.551 mmol) in ethanol and hydrogenated in a parr shaker at50 psi for 5 h. The reaction was filtered through a small pad of celiteand concentrated to give(R)-N-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-2-carboxamide(13c) (815 mg, 1.596 mmol, 103% yield) which was used in the next stepwithout further purification; ¹H NMR (300 MHz, DMSO-d₆) δ 10.13 (s, 1H),8.29 (dd, J=7.6, 2.4 Hz, 1H), 7.79 (t, J=1.8 Hz, 1H), 7.72 (dt, J=7.4,1.4 Hz, 1H), 7.60 (dt, J=8.3, 1.5 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.22(m, 1H), 7.06 (m, 1H), 5.46 (s, 1H), 3.74 (dd, J=9.1, 5.2 Hz, 1H), 3.43(m, 2H), 2.87 (m, 2H), 2.71-2.53 (m, 2H), 2.05 (m, 1H), 1.79 (dq,J=12.4, 6.5 Hz, 1H), 1.72-1.56 (m, 2H), 1.14 (s, 9H), 0.99-0.82 (m, 1H),0.74-0.54 (m, 1H), 0.35 (m, 2H), 0.04-−0.15 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −131.82; MS (ES+) 511.4 (M+1), 533.5 (M+Na), (ES−) 509.4(M−1).

Step 3: Preparation of(R)-N1-(5-chloropyridin-2-yl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(13d)

To a solution of(R)-N-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-2-carboxamide(13c) (0.763 g, 1.494 mmol) in tetrahydrofuran (50 mL) was added phenyl5-chloropyridin-2-ylcarbamate (13b) (0.446 g, 1.793 mmol) andN-ethyl-N-isopropylpropan-2-amine (1.041 mL, 5.98 mmol). The reactionmixture was heated to reflux for 16 h. The reaction was cooled to roomtemperature, diluted with ethylacetate (100 mL), washed with water (2×50mL), brine (50 mL), dried and concentrated in vacuum. The crude residuewas purified by flash column chromatography to afford(R)-N1-(5-chloropyridin-2-yl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(13d) (773 mg, 1.162 mmol, 78% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.82 (s, 1H), 9.07 (s, 1H), 8.28 (dd, J=2.7, 0.8 Hz, 1H),7.96-7.86 (m, 2H), 7.83-7.76 (m, 2H), 7.71 (dt, J=7.4, 1.5 Hz, 1H), 7.58(d, J=8.0 Hz, 1H), 7.50 (m, 1H), 7.27-7.05 (m, 2H), 5.52 (s, 1H), 4.62(d, J=7.7 Hz, 1H), 3.78-3.62 (m, 1H), 3.62-3.46 (m, 1H), 2.73-2.40 (m,2H), 2.26-2.10 (m, 1H), 1.93 (m, 3H), 1.12 (s, 10H), 0.85 (m, 1H),0.72-0.54 (m, 1H), 0.33 (m, 2H), 0.00-−0.16 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −126.74.

Step-4: Preparation of(R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)pyrrolidine-1,2-dicarboxamide(13e)

Reaction of(R)-N1-(5-chloropyridin-2-yl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(13d) (554 mg, 0.833 mmol) in ethanol (100 mL) using conc. HCl (0.694mL, 8.33 mmol) as reported in step 6 of Scheme 4 gave after purificationby flash column chromatography (silica gel 25 g, eluting with 9:1mixture of ethyl acetate and methanol in hexanes 0 to 60%)(R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)pyrrolidine-1,2-dicarboxamide(13e) (219 mg, 0.390 mmol, 46.9% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.05 (s, 1H), 8.28 (d, J=2.6 Hz, 1H),7.96-7.88 (m, 2H), 7.86 (m, 1H), 7.79 (dd, J=9.0, 2.6 Hz, 1H), 7.63(ddt, J=7.6, 5.9, 1.3 Hz, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.14 (d, J=2.0Hz, 1H), 7.12 (d, J=1.3 Hz, 1H), 4.61 (d, J=7.7 Hz, 1H), 3.66 (m, 1H),3.56 (m, 1H), 3.33-3.27 (m, 1H), 2.40-2.06 (m, 4H), 1.94 (m, 3H),1.13-0.85 (m, 2H), 0.62 (m, 1H), 0.41-0.26 (m, 2H), −0.03-−0.17 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.82; MS(ES+) 561.4, 562.4 (M+1), 583.4,585.5 (M+Na); IR (KBr) 2229 cm⁻¹; Optical rotation [α]_(D)=(+) 160.49[0.82, MeOH].

Preparation of(2R,4R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide(14h) Step 1: Preparation of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(14b)

To a solution of (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (14a)(10 g, 76 mmol) in THF:H₂O (125 mL, 2:1) was added 2.5M aqueous sodiumhydroxide (42.1 mL, 105 mmol) followed by a solution of di-tert-butyldicarbonate (22.80 g, 104 mmol) in THF:H₂O (125 mL, 2:1) and stirred atroom temperature for 32 h. The mixture was concentrated in vacuum toremove the THF and aqueous layer was added acidified with 10% aqueouspotassium hydrogen sulfate solution (150 mL). The resulting mixture wasextracted with ethyl acetate, washed with water, brine, dried, filtered,and evaporated to dryness. The resulting semi-solid was crystallizedfrom hot ethyl acetate to afford(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(14b) (13.58 g, 58.7 mmol, 77% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.41 (s, 1H, D₂O exchangeable), 4.95 (s, 1H, D₂Oexchangeable), 4.20 (q, J=5.1 Hz, 1H), 4.14-4.02 (m, 1H), 3.48 (dt,J=10.8, 5.4 Hz, 1H), 3.09 (ddd, J=10.6, 6.2, 4.2 Hz, 1H), 2.41-2.20 (m,1H), 1.81 (dt, J=12.8, 5.0 Hz, 1H), 1.37 (d, J=15.9 Hz, 9H); ¹H NMR (300MHz, MeOH-d₄) δ 4.34 (ddd, J=5.8, 4.0, 1.5 Hz, 1H), 4.30-4.22 (m, 1H),3.61 (dd, J=11.1, 5.6 Hz, 1H), 3.38-3.33 (m, 1H), 2.54-2.32 (m, 1H),2.15-1.97 (m, 1H), 1.45 (d, J=12.0 Hz, 9H); MS (ES+) 254.3 (M+Na); MS(ES−) 230.2 (M−1), 461.5 (2M−1); Optical rotation [α]_(D)=(+) 52.96[1.065, MeOH].

Step 2: Preparation of (2R,4R)-tert-butyl2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(14c)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(14b) (0.752 g, 3.25 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (1.345 g, 3.25 mmol) in tetrahydrofuran (50 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.804 g, 3.25 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%) (2R,4R)-tert-butyl2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(14c) (0.84 g, 1.340 mmol, 41.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.79 (s, 1H), 7.78 (d, J=1.9 Hz, 1H), 7.75-7.67 (m, 1H),7.62 (m, 1H), 7.51 (m, 1H), 7.20 (m, 1H), 6.90 (m, 1H), 6.72 (m, 1H),6.48 (m, 1H), 5.28 (s, 1H), 5.11 (s, 1H), 4.38-4.14 (m, 1H), 3.47 (m,1H), 3.31-3.19 (m, 1H), 2.76-2.23 (m, 3H), 1.99 (m, 1H), 1.12 (s, 18H),1.00-0.79 (m, 2H), 0.76-0.56 (m, 1H), 0.35 (m, 2H), −0.00-−0.16 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.33; MS (ES+) 649.5 (M+Na), (ES−) 625.5(M−1).

Step 3: Preparation of (2R,4R)-tert-butyl4-acetoxy-2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate(14d)

To a solution of (2R,4R)-tert-butyl2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(14c) (0.8 g, 1.276 mmol) in dichloromethane (30 mL) was added DIPEA(0.669 mL, 3.83 mmol), acetic anhydride (0.145 mL, 1.532 mmol), DMAP(7.80 mg, 0.064 mmol) and stirred at room temperature overnight. Thereaction was diluted with dichloromethane (100 mL), washed with water(2×25 mL), brine (25 mL), dried and concentrated. The crude residueobtained was purified by flash column chromatography (silica gel 12 g,eluting with ethyl acetate in hexanes 0 to 50%) to afford(2R,4R)-tert-butyl4-acetoxy-2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate(14d) (324 mg, 0.484 mmol, 38.0% yield) as a white semi solid; 1H NMR(300 MHz, DMSO-d₆) δ 9.63 (s, 1H), 7.78 (m, 1H), 7.76-7.55 (m, 3H), 7.51(m, 1H), 7.21 (m, 2H), 5.49 (s, 1H), 5.09 (t, J=7.2 Hz, 1H), 4.42 (2sets of dd, J=32.7, 7.2 Hz, 1H for rotamers), 3.76-3.59 (m, 1H),3.49-3.35 (m, 1H), 2.75-2.38 (m, 2H), 2.09-1.95 (m, 1H), 1.87 (2S, 3Hfor rotamers), 1.36 (2s, 9H for rotamers), 1.12 (s, 10H), 1.08-1.00 (m,1H), 1.00-0.80 (m, 1H), 0.72-0.51 (m, 1H), 0.44-0.24 (m, 2H), −0.06 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −125.32; MS (ES+) 691.6 (M+Na), (ES−)667.6 (M−1); Optical rotation [α]_(D)=(−) 48.0 [0.125, MeOH].

Step-4: Preparation of(3R,5R)-5-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-ylacetate (14e) and(2R,4R)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(14f)

Reaction of (2R,4R)-tert-butyl4-acetoxy-2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidine-1-carboxylate(14d) (0.32 g, 0.478 mmol) in ethanol (10 mL) using conc. HCl (0.399 mL,4.78 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel 12 g, eluting with CMA-80 inchloroform 0 to 60%) gave

-   -   1.        (3R,5R)-5-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-yl        acetate (14e) (90 mg, 0.194 mmol, 40.5% yield); 1H NMR (300 MHz,        DMSO-d6) δ 10.04 (d, J=2.0 Hz, 1H), 8.24-8.11 (m, 1H), 7.84 (t,        J=1.6 Hz, 1H), 7.64 (tt, J=7.6, 1.3 Hz, 2H), 7.47 (t, J=7.8 Hz,        1H), 7.27-7.06 (m, 2H), 5.07 (m, 1H), 3.81 (d, J=9.4 Hz, 1H),        3.46 (m, 1H), 3.18 (m, 1H), 2.91 (m, 1H), 2.26 (m, 5H), 2.06 (m,        1H), 1.75 (s, 3H), 1.03 (m, 2H), 0.64 (m, 1H), 0.42-0.28 (m,        2H), −0.07 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ −132.66.        MS(ES+) 465.4 (M+1), 487.4 (M+Na), (ES−) 463.4 (M−1), 499.5        (M+Cl).    -   2.        (2R,4R)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide        (14f) (100 mg, 0.237 mmol, 49.5% yield); ¹H NMR (300 MHz,        DMSO-d₆) δ 10.19 (s, 1H), 8.42-8.22 (m, 1H), 7.86 (t, J=1.7 Hz,        1H), 7.74-7.59 (m, 2H), 7.47 (m, 1H), 7.25-6.94 (m, 2H), 4.67        (d, J=3.3 Hz, 1H), 4.16 (m, 1H), 3.84-3.60 (m, 1H), 3.00 (m,        1H), 2.72 (dd, J=10.6, 3.0 Hz, 1H), 2.43-2.03 (m, 6H), 1.83 (dt,        J=13.0, 3.9 Hz, 1H), 1.14-0.88 (m, 2H), 0.76-0.51 (m, 1H),        0.46-0.25 (m, 2H), −0.03-−0.10 (m, 2H); ¹⁹F NMR (282 MHz,        DMSO-d₆) δ −133.44; MS (ES+) 423.4 (M+1), 445.4 (M+Na), (ES−)        457.4 (M+Cl).

Step 5: Preparation of Preparation of(2R,4R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide(14h)

Reaction of(2R,4R)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(14f) (92 mg, 0.218 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (54.1 mg, 0.218 mmol) as reported in step3 of Scheme 13 after purification by flash column chromatography (silicagel 12 g, eluting with 0-100% CMA-80 in chloroform) afforded(2R,4R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide(14h) (34 mg, 0.059 mmol, 27.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.67 (s, 1H), 9.16 (s, 1H), 8.31-8.26 (m, 1H), 8.01 (d,J=7.5 Hz, 1H), 7.94-7.83 (m, 2H), 7.79 (dd, J=9.0, 2.7 Hz, 1H), 7.63 (m,2H), 7.46 (t, J=7.8 Hz, 1H), 7.13 (dd, J=7.4, 2.0 Hz, 2H), 5.31 (d,J=4.7 Hz, 1H), 4.54 (m, 1H), 4.31 (q, J=4.9 Hz, 1H), 3.73 (m, 1H), 3.51(dd, J=10.5, 4.2 Hz, 1H), 2.47-2.28 (m, 3H), 2.28-2.10 (m, 2H), 1.89 (m,1H), 1.01 (m, 2H), 0.63 (m, 1H), 0.34 (m, 2H), −0.03-−0.17 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −128.70; MS (ES+) 577.5, 579.5 (M+1); IR (KBr)2229 cm¹.

Preparation of(3R,5R)-5-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-1-(5-chloropyridin-2-ylcarbamoyl)pyrrolidin-3-ylacetate (14g)

Reaction of(3R,5R)-5-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-ylacetate (14e) (81 mg, 0.174 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (43.4 mg, 0.174 mmol) as reported in step3 of Scheme 13 after purification by flash column chromatography (silicagel 12 g, eluting with 0-100% CMA-80 in chloroform) afforded(3R,5R)-5-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-1-(5-chloropyridin-2-ylcarbamoyl)pyrrolidin-3-ylacetate (14g) (24 mg, 0.039 mmol, 22.23% yield) as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.18 (s, 1H), 8.30 (d, J=2.6 Hz, 1H),7.91 (dd, J=9.0, 0.8 Hz, 1H), 7.86-7.79 (m, 2H), 7.75 (dd, J=7.6, 2.2Hz, 1H), 7.63 (m, 2H), 7.46 (m, 1H), 7.23-7.10 (m, 2H), 5.19 (q, J=4.6,3.7 Hz, 1H), 4.72 (d, J=8.7 Hz, 1H), 3.88 (dd, J=11.7, 5.2 Hz, 1H), 3.75(d, J=11.7 Hz, 1H), 2.48-2.40 (m, 1H), 2.32 (m, 2H), 2.22 (m, 3H), 1.87(s, 3H), 1.12-0.91 (m, 2H), 0.72-0.50 (m, 1H), 0.42-0.28 (m, 2H),−0.03-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −126.76; MS (ES−)617.4 (M−1), 653.3, 655.3 (M+Cl); Optical rotation [α]_(D)=(+) 109.1[0.165, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-cyanophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(15f) Step 1: Preparation of(2R,4R)-1-(benzyloxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(15b)

To a slurry of sodium hydride (60% dispersion in oil, 2.262 g, 56.5mmol) in tetrahydrofuran (30 mL) at −10° C. was added a solution of(2R,4R)-1-(benzyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(15a) (2.5 g, 9.42 mmol) in THF (60 mL). The reaction was stirred for 30min, followed by the addition of dimethyl sulfate (0.901 mL, 9.42 mmol)and stirred at room temperature for 16 h. The reaction mixture wasquenched with saturated aqueous ammonium chloride and concentrated invacuum to remove THF. The reaction mixture was basified, washed withether, acidified and extracted with ethyl acetate (2×100 mL). Thecombined ethyl acetate layer was washed with water (50 mL), brine (50mL), dried, filtered and evaporated in vacuum to obtain(2R,4R)-1-(benzyloxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(15b) (2.138 g, 7.66 mmol, 81% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.56 (s, 1H), 7.55-7.12 (m, 5H), 5.23-4.88 (m, 2H), 4.29(ddd, J=21.9, 9.4, 3.0 Hz, 1H), 3.95 (qt, J=5.3, 2.7 Hz, 1H), 3.61 (ddd,J=15.6, 11.5, 5.4 Hz, 1H), 3.31 (m, 1H), 3.17 (2s, 3H, for rotamers),2.42-2.24 (m, 1H), 2.17-2.01 (m, 1H); MS (ES−) 278.2 (M−1); Opticalrotation [α]_(D)=(+) 33.81 [0.775, MeOH].

Step 2: Preparation of (2R,4R)-benzyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(15c)

Reaction of(2R,4R)-1-(benzyloxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(15b) (1.52 g, 5.44 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (2.251 g, 5.44 mmol) in tetrahydrofuran (75 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (1.346 g, 5.44 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%) (2R,4R)-benzyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(15c) (3.15 g, 4.67 mmol, 86% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.54 (2s, 1H, for rotamers), 7.86 (m, 1H), 7.79 (m, 1H), 7.71(m, 1H), 7.65-7.56 (m, 1H), 7.52 (m, 1H), 7.38 (m, 2H), 7.19 (m, 5H),5.50 (2s, 1H, for rotamers), 5.18-4.93 (m, 2H), 4.54-4.33 (m, 1H),4.05-3.93 (m, 2H), 3.75-3.59 (m, 1H), 3.49-3.39 (m, 1H), 3.19 (2s, 3H,for rotamers), 2.51 (m, 2H), 2.12-2.00 (m, 1H), 1.17-1.01 (m, 10H),0.98-0.81 (m, 1H), 0.71-0.55 (m, 1H), 0.42-0.25 (m, 2H), 0.01-−0.13 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −126.94, −127.36; MS (ES+) 675.5(M+1), 697.5, 698.5 (M+Na), (ES−) 673.5 (M−1), 709.4, 710.4 (M+Cl);Optical rotation [α]_(D)=(−) 58.2 [0.165, MeOH].

Step 3: Preparation of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(15d)

Debenzylation by hydrogenation of (2R,4R)-benzyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(15c) (3.05 g, 4.52 mmol) in ethanol (100 mL), using palladium on carbon10% (0.265 g, 0.249 mmol) as catalyst according to procedure reported instep 2 of Scheme 13 gave(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(15d) (2.4 g, 4.44 mmol, 98% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.09 (d, J=2.2 Hz, 1H), 8.29 (dd, J=7.7, 2.4 Hz, 1H), 7.80(t, J=1.8 Hz, 1H), 7.71 (dt, J=7.4, 1.3 Hz, 1H), 7.62 (dt, J=8.3, 1.5Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.21 (dd, J=10.8, 8.7 Hz, 1H),7.10-7.01 (m, 1H), 5.47 (s, 1H), 3.95-3.81 (m, 1H), 3.74 (dd, J=8.1, 5.1Hz, 1H), 3.11 (s, 3H), 3.08-2.97 (m, 1H), 2.89 (dd, J=11.1, 2.4 Hz, 1H),2.75-2.56 (m, 2H), 2.13-2.01 (m, 2H), 1.14 (s, 10H), 1.12-1.04 (m, 1H),0.96-0.80 (m, 1H), 0.72-0.53 (m, 1H), 0.43-0.27 (m, 2H), 0.00-−0.15 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −132.45; MS (ES+) 541.5 (M+1), (ES−)575.4 (M+Cl); Optical rotation [α]_(D)=(−) 67.1 [0.155, MeOH].

Step-4: Preparation of(2R,4R)-N1-(4-cyanophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(15e)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(15d) (0.5 g, 0.925 mmol) in tetrahydrofuran (20 mL),4-isocyanatobenzonitrile (0.267 g, 1.849 mmol) using DIPEA (0.646 mL,3.70 mmol) as base using reaction and workup conditions as reported instep 9 of Scheme 1 gave(2R,4R)-N1-(4-cyanophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(15e) (514 mg, 0.751 mmol, 81% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.51 (d, J=1.3 Hz, 1H), 8.85 (s, 1H), 7.90-7.84 (m, 1H), 7.78(t, J=1.6 Hz, 1H), 7.77-7.66 (m, 5H), 7.62-7.57 (m, 1H), 7.50 (t, J=7.8Hz, 1H), 7.19 (dd, J=10.3, 8.7 Hz, 1H), 7.14-7.06 (m, 1H), 5.50 (s, 1H),4.57 (dd, J=9.1, 4.1 Hz, 1H), 4.11-4.06 (m, 1H), 3.76 (dd, J=10.6, 5.2Hz, 1H), 3.65 (dd, J=10.2, 2.9 Hz, 2H), 3.23 (s, 3H), 2.76-2.53 (m, 1H),2.48-2.31 (m, 1H), 2.18-2.05 (m, 1H), 1.13 (s, 9H), 1.11-1.01 (m, 1H),0.98-0.80 (m, 1H), 0.72-0.55 (m, 1H), 0.41-0.26 (m, 2H), −0.02-−0.14 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.51; MS: (ES+) 685.5 (M+1), 707.5,709.7 (M+Na), (ES−) 719.5, 721.1 (M+Cl); Optical rotation [α]_(D)=(−)4.21 [0.19, MeOH].

Step 5: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-cyanophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(15f)

Reaction of(2R,4R)-N1-(4-cyanophenyl)-N2-(5-((R)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(15e) (445 mg, 0.650 mmol) in ethanol (20 mL) using conc. HCl (0.542 mL,6.50 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel 12 g, eluting with CMA-80 inchloroform 0 to 60%) gave(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-cyanophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(15f) (300 mg, 0.517 mmol, 80% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.46 (s, 1H), 8.83 (s, 1H), 7.89-7.81 (m, 2H), 7.78-7.60 (m,6H), 7.46 (t, J=7.8 Hz, 1H), 7.18-7.07 (m, 2H), 4.56 (dd, J=9.1, 4.1 Hz,1H), 4.17-3.98 (m, 1H), 3.77 (dd, J=10.5, 5.2 Hz, 1H), 3.63 (dd, J=10.4,3.4 Hz, 1H), 3.22 (s, 3H), 2.41-2.14 (m, 5H), 2.14-2.00 (m, 1H),1.09-0.92 (m, 2H), 0.76-0.49 (m, 1H), 0.41-0.27 (m, 2H), −0.04-−0.19 (m,2H); 19F NMR (282 MHz, DMSO-d6) δ −128.39; MS (ES+) 603.5, 604.5 (M+Na),(ES−) 615.6, 617.4 (M+Cl); Optical rotation [α]_(D)=(+) 108.68 [0.265,MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide(16b) Step 1: Preparation of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide(16a)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(15d) (0.5 g, 0.925 mmol) in tetrahydrofuran (20 mL), phenyl1-isocyanato-4-methoxybenzene (0.240 mL, 1.849 mmol), DIPEA (0.646 mL,3.70 mmol) using reaction and workup conditions as reported in step 9 ofScheme 1 gave(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide(16a) (552 mg, 0.800 mmol, 87% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.50 (s, 1H), 8.28 (s, 1H), 8.00 (dd, J=7.7, 2.4 Hz, 1H),7.79 (t, J=1.7 Hz, 1H), 7.71 (m, 1H), 7.60 (m, 1H), 7.50 (t, J=7.8 Hz,1H), 7.43-7.34 (m, 2H), 7.19 (m, 1H), 6.87-6.79 (m, 2H), 5.50 (s, 1H),4.52 (dd, J=9.2, 3.7 Hz, 1H), 4.07 (m, 1H), 3.70 (s, 3H), 3.65 (m, 2H),3.22 (s, 3H), 2.75-2.48 (m, 2H), 2.32 (m, 1H), 2.23-2.11 (m, 1H), 1.13(s, 10H), 1.00-0.79 (m, 1H), 0.43-0.25 (m, 2H), 0.63 (m, 1H), 0.43-0.25(m, 2H), −0.01-−0.15 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.51; MS(ES+) 690.5 (M+1), 712.5, 713.5 (M+Na), (ES−) 724.4, 726.6 (M+Cl);Optical rotation [α]_(D)=(−) 17.78 [0.36, MeOH].

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide(16b)

Reaction of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide(16a) (485 mg, 0.703 mmol) in ethanol (20 mL) using conc. HCl (0.586 mL,7.03 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel, eluting with CMA-80 inchloroform 0 to 100%) gave(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-methoxy-N1-(4-methoxyphenyl)pyrrolidine-1,2-dicarboxamide(16b) (19 mg, 0.032 mmol, 4.61% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.26 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.86(t, J=1.7 Hz, 1H), 7.71-7.57 (m, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.41-7.32(m, 2H), 7.13 (d, J=8.0 Hz, 2H), 6.88-6.75 (m, 2H), 4.51 (dd, J=9.3, 3.7Hz, 1H), 4.11-3.99 (m, 1H), 3.70 (s, 3H), 3.67 (m, 1H), 3.64-3.56 (m,1H), 3.22 (s, 3H), 2.38-2.11 (m, 6H), 1.11-0.94 (m, 2H), 0.73-0.55 (m,1H), 0.40-0.24 (m, 2H), −0.01-−0.21 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ −129.61; MS (ES+) 586.5 (M+1), 608.5, 610.6 (M+Na), (ES−) 620.5, 622.5(M+Cl); IR (KBr) 2228 cm¹; Analysis calculated for C₃₃H₃₆FN₅O₄.0.5H₂O;C, 66.65; H, 6.27; N, 11.78. Found; C, 66.83; H, 6.19; N, 11.71; Opticalrotation [α]_(D)=(+) 95.48 [0.155, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-methoxy-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(17b) Step 1: Preparation of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(17a)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(15d) (0.5 g, 0.925 mmol) in tetrahydrofuran (20 mL), 4-chlorophenylisocyanate (1n) (0.237 mL, 1.849 mmol), DIPEA (0.646 mL, 3.70 mmol)using reaction and workup conditions as reported in step 9 of Scheme 1gave(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxy-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(17a) (555 mg, 0.799 mmol, 86% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.52-9.44 (m, 1H), 8.53 (s, 1H), 7.96-7.88 (m, 1H), 7.79 (t,J=1.7 Hz, 1H), 7.71 (dt, J=7.5, 1.3 Hz, 1H), 7.63-7.46 (m, 4H),7.33-7.25 (m, 2H), 7.19 (dd, J=10.4, 8.8 Hz, 1H), 7.11 (m, 1H), 5.50 (s,1H), 4.54 (m, 1H), 4.10-4.05 (m, 1H), 3.72 (m, 1H), 3.68-3.57 (m, 1H),3.22 (s, 3H), 2.63 (m, 2H), 2.42-2.26 (m, 1H), 2.12 (m, 1H), 1.13 (s,9H), 1.12-1.01 (m, 1H), 0.98-0.76 (m, 1H), 0.72-0.56 (m, 1H), 0.43-0.22(m, 2H), −0.02-−0.16 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.06; MS:(ES+) 694.5 (M+H), 716.5, 718.5 (M+Na), (ES−) 728.5, 730.4 (M+Cl);Optical rotation [α]_(D)=(−) 17.31 [0.335, MeOH].

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-methoxy-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(17b)

Reaction of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(17a) (478 mg, 0.689 mmol) in ethanol (20 mL) using conc. HCl (0.574 mL,6.89 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel, eluting with CMA-80 inchloroform 0 to 100%)(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(17b) (52 mg, 8.3%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.67(s, 1H), 9.21 (s, 3H), 8.56 (s, 1H), 7.89 (m, 2H), 7.84 (m, 1H),7.70-7.58 (m, 2H), 7.58-7.52 (m, 2H), 7.36 (m, 1H), 7.32-7.26 (m, 2H),7.09 (m, 1H), 4.56 (dd, J=9.2, 4.0 Hz, 1H), 4.13-4.04 (m, 1H), 3.74 (dd,J=10.5, 5.2 Hz, 1H), 3.62 (d, J=10.6 Hz, 1H), 3.22 (s, 3H), 2.60-2.53(m, 1H), 2.47-2.32 (m, 1H), 2.08 (m, 1H), 1.15-0.99 (m, 2H), 0.78-0.57(m, 1H), 0.45-0.17 (m, 2H), 0.17-−0.10 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −125.67; MS (ES+) 612.5, 614.4 (M+Na), (ES−) 624.4, (M+Cl);Optical rotation [α]_(D)=(+) 71.88 [0.32, MeOH]; Analysis calculatedfor: C₃₂H₃₃ClFN₅O₃.HCl.2H₂O; C, 58.01; H, 5.78; N, 10.57. Found: C,58.21; H, 5.41; N, 10.24; IR (KBr) 2233 cm¹.

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(18b) Step 1: Preparation of((2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(18a)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(15d) (0.475 g, 0.879 mmol) in tetrahydrofuran (20 mL), phenyl5-chloropyridin-2-ylcarbamate (13b) (0.437 g, 1.757 mmol), DIPEA (0.614mL, 3.51 mmol) using reaction and workup conditions as reported in step3 of Scheme 13 gave((2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(18a) (484 mg, 0.696 mmol, 79% yield) as white powder; ¹H NMR (300 MHz,DMSO-d₆) δ 9.49 (s, 1H), 9.17 (s, 1H), 8.30 (d, J=2.7 Hz, 1H), 7.93-7.86(m, 2H), 7.84-7.77 (m, 2H), 7.71 (dt, J=7.5, 1.3 Hz, 1H), 7.59 (dt,J=8.2, 1.6 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.19 (dd, J=10.4, 8.7 Hz,1H), 7.14-7.06 (m, 1H), 5.50 (s, 1H), 4.59 (dd, J=9.1, 3.9 Hz, 1H), 4.04(m, 1H), 3.81-3.63 (m, 2H), 3.21 (s, 3H), 2.75-2.52 (m, 2H), 2.48-2.29(m, 1H), 2.11 (m, 1H), 1.13 (s, 10H), 0.97-0.80 (m, 1H), 0.72-0.49 (m,1H), 0.40-0.27 (m, 2H), −0.01-0.15 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−127.91; MS (ES+) 695.5 (M+1), 717.5, 719.5 (M+Na), (ES−) 729.5, 731.5(M+Cl); IR (KBr) 2230 cm-; Optical rotation [α]_(D)=(−) 19.10 [0.335,MeOH]; CHN calculated for: C₃₅H₄₀ClFN₆O₄S. 0.5H₂O; C, 59.69; H, 5.87; N,11.93. Found: C, 59.74; H, 5.75; N, 11.79.

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(18b)

Reaction of((2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(18a) (406 mg, 0.584 mmol) in ethanol (20 mL) using conc. HCl (0.487 mL,5.84 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel, eluting with CMA-80 inchloroform 0 to 100%)(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(18b) (60 mg, 10%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.45(s, 1H), 9.15 (s, 1H), 8.30 (dd, J=2.6, 0.8 Hz, 1H), 7.93-7.84 (m, 3H),7.81 (dd, J=9.0, 2.7 Hz, 1H), 7.63 (ddt, J=7.5, 5.7, 1.3 Hz, 2H), 7.46(t, J=7.8 Hz, 1H), 7.15 (d, J=1.3 Hz, 1H), 7.13 (d, J=2.9 Hz, 1H), 4.57(dd, J=9.2, 3.9 Hz, 1H), 4.10-3.97 (m, 1H), 3.82-3.62 (m, 2H), 3.21 (s,3H), 2.41-2.18 (m, 5H), 2.17-2.00 (m, 1H), 1.08-0.94 (m, 2H), 0.72-0.53(m, 1H), 0.42-0.25 (m, 2H), −0.03-−0.16 (m, 2H); 19F NMR (282 MHz,DMSO-d₆) δ −128.61; MS (ES+) 591.5, 593.4 (M+1), (ES−) 625.3, 627.6(M+Cl); Analysis calculated for: C₃₁H₃₂ClFN₆O₃.0.25H₂O: C, 62.52; H,5.50; N, 14.11. Found: C, 62.53; H, 5.52; N, 13.89; Optical rotation[α]_(D)=(+) 95.38 [0.26, MeOH].

Preparation of(2R,4R)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(19c) Step 1: Preparation of(2R,4R)-4-azido-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(19a)

To a solution of(2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(9b) (0.502 g, 0.738 mmol) and triphenylphosphine (0.581 g, 2.214 mmol)in tetrahydrofuran (15 mL) at 0° C. was added a mixture of diphenylphosphorazidate (0.477 mL, 2.214 mmol) and diisopropyl azodicarboxylate(0.430 mL, 2.214 mmol) in tetrahydrofuran (5 mL) over a period of 30mins. Reaction was allowed to room temperature stirred for 24 h, dilutedwith ethyl acetate (150 mL), washed with water (2×25 mL), brine (25 mL),dried, filtered and concentrated in vacuum. The crude residue waspurified by flash column chromatography (silica gel, 40 g eluting with(9:1) ethyl acetate and methanol in hexanes 0 to 100%) to afford(2R,4R)-4-azido-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(19a) (88 mg, 0.125 mmol, 16.91% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.78 (s, 1H), 8.06 (s, 1H), 7.99 (m, 1H),7.91 (m, 1H), 7.76 (m, 4H), 7.51 (m, 2H), 7.39 (m, 1H), 7.38-7.26 (m,1H), 5.71 (s, 1H), 4.79 (m, 2H), 4.35-4.15 (m, 1H), 4.03 (m, 1H), 3.76(d, J=10.2 Hz, 1H), 2.37-2.23 (m, 1H), 1.40-1.35 (m, 1H), 1.33 (s, 11H),1.23-1.01 (m, 1H), 0.84 (m, 1H), 0.62-0.46 (m, 2H), 0.21-0.06 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −126.67.

Step 2: Preparation of(2R,4R)-4-amino-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(19c)

Hydrogenation of(2R,4R)-4-azido-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(19a) (0.08 g, 0.113 mmol) in ethanol (10 mL), using palladium on carbon10% (0.012 g, 0.011 mmol) as catalyst for six hours according toprocedure reported in step 2 of Scheme 13 gave(2R,4R)-4-amino-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(19c) (60 mg, 0.088 mmol, 78% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.46 (s, 1H), 8.11 (d, J=7.3 Hz, 1H), 7.79 (m, 1H), 7.70 (m,1H), 7.63-7.46 (m, 4H), 7.26 (m, 2H), 7.23-7.13 (m, 1H), 7.05 (m, 1H),5.48 (s, 1H), 4.44 (dd, J=9.1, 5.1 Hz, 1H), 3.74-3.40 (m, 3H), 2.76-2.21(m, 4H), 1.78 (m, 1H), 1.13 (s, 10H), 1.02-0.74 (m, 1H), 0.74-0.51 (m,1H), 0.34 (m, 2H), −0.06 (m, 2H); MS (ES+) 679.6 (M+1); 702.5 (M+Na).

Step-3: Preparation of(2R,4R)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(19c)

Reaction of(2R,4R)-4-amino-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(19c) (0.052 g, 0.077 mmol) in ethanol (5 mL) using conc. HCl (0.064 mL,0.766 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel, eluting with CMA-80 inchloroform 0 to 100%)(2R,4R)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(19c) (12 mg, 0.021 mmol, 27.3% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.15-7.99 (m, 1H), 7.86 (t, J=1.6 Hz, 1H),7.67-7.60 (m, 2H), 7.57-7.42 (m, 3H), 7.32-7.23 (m, 2H), 7.15-7.06 (m,2H), 4.43 (dd, J=9.0, 5.3 Hz, 1H), 3.64 (dd, J=9.6, 5.6 Hz, 1H),3.58-3.47 (m, 1H), 2.41-2.27 (m, 4H), 2.25-2.18 (m, 2H), 1.84-1.63 (m,1H), 1.12-0.93 (m, 2H), 0.72-0.55 (m, 1H), 0.34 (m, 2H), −0.01-−0.14 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.51; MS (ES−) 573.5, 575.4 (M−1);Optical rotation [α]_(D)=(+) 85.0 [0.08, MeOH].

Preparation of(R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide(20b) Step 1: Preparation of(R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide(20a)

To a solution of(2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(9b) (50 mg, 0.074 mmol) in dichloromethane (10 mL) at room temperaturewas added sodium bicarbonate (24.70 mg, 0.294 mmol), Dess-MartinPeriodinane (100 mg, 0.235 mmol) and stirred for 30 mins. The reactionwas diluted with dichloromethane (50 mL), washed with water (2×25 mL),brine (25 mL), dried, filtered and concentrated in vacuum to dryness.The crude residue obtained was purified by flash column chromatography(silica gel, 4 g eluting with CMA 80 in chloroform 0 to 100%) afford(R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide(20a) (40 mg, 0.059 mmol, 80% yield) as nearly colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.57 (s, 1H), 8.08-7.98 (m, 1H),7.94 (m, 1H), 7.85-7.66 (m, 2H), 7.61-7.45 (m, 3H), 7.31 (m, 2H),7.26-7.16 (m, 1H), 7.13 (m, 1H), 5.51 (s, 1H), 5.10 (d, J=9.7 Hz, 1H),4.27-4.10 (m, 1H), 3.98 (d, J=17.4 Hz, 1H), 3.40 (m, 2H), 2.63-2.38 (m,2H), 1.11 (s, 10H), 0.98-0.79 (m, 1H), 0.72-0.51 (m, 1H), 0.40-0.25 (m,2H), −0.00-−0.21 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −126.75; MS (ES+)700.4 (M+23), (ES−) 676.4 (M−1); 712.4, 714.4 (M+Cl).

Step 2: Preparation of(R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide(20b)

Reaction of(R)-N1-(4-chlorophenyl)-N2-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide(20a) (35 mg, 0.052 mmol) in ethanol (5 mL) using conc. HCl (0.043 mL,0.516 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel, eluting with CMA-80 inchloroform 0 to 100%)(R)-N2-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-oxopyrrolidine-1,2-dicarboxamide(20b) (20 mg, 0.035 mmol, 67.5% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.56 (s, 1H), 8.04-7.96 (m, 1H), 7.86 (t,J=1.8 Hz, 1H), 7.63 (ddt, J=7.6, 5.9, 1.4 Hz, 2H), 7.59-7.51 (m, 2H),7.45 (t, J=7.8 Hz, 1H), 7.34-7.27 (m, 2H), 7.18-7.08 (m, 2H), 5.10 (dd,J=10.0, 2.2 Hz, 1H), 4.19 (d, J=17.6 Hz, 1H), 3.98 (d, J=17.5 Hz, 1H),3.11 (m, 1H), 2.61-2.51 (m, 1H), 2.36-2.27 (m, 2H), 2.27-2.15 (m, 2H),1.09-0.90 (m, 2H), 0.70-0.51 (m, 1H), 0.37-0.27 (m, 2H), −0.00-−0.13 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.99; MS (ES+) 596.5 (M+Na), (ES−)610.4 (M+Cl).

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide(21d) Step 1: Preparation of (2R,4R)-benzyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(21a)

Reaction of(2R,4R)-1-(benzyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(15a) (1.5 g, 5.65 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (2.339 g, 5.65 mmol) in tetrahydrofuran (50 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (1.398 g, 5.65 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%) (2R,4R)-benzyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(21a) (2.396 g, 3.63 mmol, 64.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.79 (2s, 1H, rotamers), 8.04 (d, J=7.3 Hz, 1H), 7.79(s, 1H), 7.71 (d, J=7.4 Hz, 1H), 7.60 (m, 1H), 7.51 (m, 1H), 7.37 (m,2H), 7.26-7.04 (m, 5H), 5.50 (d, J=17.5 Hz, 1H), 5.29 (s, 1H), 5.14-4.89(m, 2H), 4.53-4.34 (m, 1H), 4.27 (s, 1H), 3.71-3.47 (m, 2H), 3.47-3.24(m, 1H), 2.77-2.26 (m, 2H), 1.88 (m, 1H), 1.16-1.01 (m, 10H, rotamers),0.98-0.77 (m, 1H), 0.73-0.53 (m, 1H), 0.41-0.26 (m, 2H), −0.02-−0.16 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.76, −127.94; MS (ES+) 683.6(M+Na), (ES−) 695.6 (M+Cl); Optical rotation [α]_(D)=(−) 75.0 [0.16,MeOH].

Step 2: Preparation of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(21b)

Debenzylation by hydrogenation of (2R,4R)-benzyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(21a) (2.35 g, 3.56 mmol) in ethanol (100 mL), using palladium on carbon10% (0.378 g, 0.356 mmol) as catalyst according to procedure reported instep 2 of Scheme 13 gave(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide (21b) (1.61g, 3.06 mmol, 86% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.24 (s, 1H), 8.36 (dd, J=7.8, 2.4 Hz, 1H), 7.79 (t, J=1.7 Hz, 1H),7.72 (m, 1H), 7.60 (m, 1H), 7.51 (m, 1H), 7.21 (dd, J=10.8, 8.7 Hz, 1H),7.09-6.99 (m, 1H), 5.46 (s, 1H), 4.70 (d, J=3.3 Hz, 1H), 4.22-4.10 (m,1H), 3.84-3.64 (m, 1H), 3.00 (m, 1H), 2.79-2.68 (m, 2H), 2.68-2.52 (m,2H), 2.21-2.07 (m, 1H), 1.84 (m, 1H), 1.14 (s, 10H), 1.01-0.76 (m, 1H),0.75-0.54 (m, 1H), 0.44-0.25 (m, 2H), −0.02-−0.23 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −132.73; MS (ES+) 527.5 (M+1), 549.5 (M+Na), (ES−) 525.5(M−1), 561.5 (M+Cl); Optical rotation [α]_(D)=(−) 0.44 [0.15, MeOH].

Step 3: Preparation of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide(21c)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(21b) (160 mg, 0.304 mmol) and phenyl isocyanate (0.040 mL, 0.365 mmol)in tetrahydrofuran (10 mL) using reaction and workup conditions asreported in step 9 of Scheme 1 gave(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide(21c) (176 mg, 0.273 mmol, 90% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.67 (s, 1H), 8.37 (s, 1H), 8.14-8.02 (m, 1H), 7.79 (t, J=1.7Hz, 1H), 7.70 (dt, J=7.4, 1.3 Hz, 1H), 7.59 (dt, J=8.1, 1.6 Hz, 1H),7.55-7.44 (m, 3H), 7.29-7.10 (m, 3H), 7.12-7.02 (m, 1H), 6.94 (tt,J=7.3, 1.2 Hz, 1H), 5.50 (s, 1H), 5.34 (d, J=4.4 Hz, 1H), 4.51 (dd,J=9.1, 4.5 Hz, 1H), 4.42-4.27 (m, 1H), 3.67 (dd, J=10.1, 5.1 Hz, 1H),3.52 (m, 1H), 2.74-2.52 (m, 2H), 2.44-2.29 (m, 1H), 1.93 (dd, J=11.0,6.5 Hz, 1H), 1.13 (s, 10H), 1.00-0.79 (m, 1H), 0.71-0.55 (m, 1H),0.42-0.26 (m, 2H), 0.02-−0.15 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.67; MS: (ES+) 646.5 (M+1), 668.5 (M+Na), (ES−) 644.5 (M−1), 680.5(M+Cl); Optical rotation [α]_(D)=(−) 37.42 [0.155, MeOH].

Step-4: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide(21d)

Reaction of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide(21c) (160 mg, 0.248 mmol) in ethanol (10 mL) using conc. HCl (0.206 mL,2.478 mmol) as reported in step 6 of Scheme 4 gave(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-phenylpyrrolidine-1,2-dicarboxamide(21d) (50 mg, 0.092 mmol, 37.3% yield) as a colorless solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.36 (s, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.86(t, J=1.7 Hz, 1H), 7.68-7.58 (m, 2H), 7.55-7.39 (m, 3H), 7.29-7.17 (m,1H), 7.12 (d, J=9.5 Hz, 2H), 6.99-6.85 (m, 1H), 5.30 (d, J=4.5 Hz, 1H),4.50 (dd, J=9.1, 4.5 Hz, 1H), 4.34 (s, 1H), 3.68 (dd, J=10.1, 5.1 Hz,1H), 3.50 (m, 1H), 2.38-2.19 (m, 6H), 1.98-1.84 (m, 1H), 1.10-0.94 (m,2H), 0.70-0.55 (m, 1H), 0.39-0.28 (m, 2H), −0.02-−0.12 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −129.38; MS (ES+) 564.4 (M+Na); Analysis calculatedfor C₃₁H₃₂FN₅O₃.0.25H₂O: C, 67.62; H, 6.04; N, 12.72. Found: C, 67.72;H, 6.10; N, 12.60; Optical rotation [α]_(D)=(+) 90.3 [0.32, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide(22b) Step 1: Preparation of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide(22a)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(21b) (160 mg, 0.304 mmol) and p-tolyl isocyanate (0.046 mL, 0.365 mmol)in tetrahydrofuran (10 mL) using reaction and workup conditions asreported in step 9 of Scheme 1 gave(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide(22a) (154 mg, 0.233 mmol, 77% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.65 (s, 1H), 8.29 (s, 1H), 8.10 (dd, J=7.7, 2.4 Hz, 1H),7.79 (t, J=1.7 Hz, 1H), 7.70 (dt, J=7.4, 1.4 Hz, 1H), 7.59 (dt, J=8.1,1.6 Hz, 1H), 7.55-7.45 (m, 1H), 7.42-7.31 (m, 2H), 7.19 (dd, J=10.6, 8.7Hz, 1H), 7.10-6.98 (m, 3H), 5.51 (s, 1H), 5.32 (d, J=3.7 Hz, 1H), 4.50(d, J=4.7 Hz, 1H), 4.41-4.27 (m, 1H), 3.63 (d, J=5.1 Hz, 1H), 3.55-3.46(m, 1H), 2.64 (m, 1H), 2.61-2.51 (m, 1H), 2.42-2.28 (m, 1H), 2.22 (m,3H), 1.92 (m, 1H), 1.14 (d, 9H, rotamers), 1.12-1.00 (m, 1H), 0.98-0.81(m, 1H), 0.72-0.55 (m, 1H), 0.44-0.29 (m, 2H), −0.01-−0.13 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −128.93; MS: (ES+) 682.5 (M+Na), (ES−) 658.6(M−1), 694.6 (M+Cl); Optical rotation [α]_(D)=(−)14.66 [0.15, MeOH].

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide(22b)

Reaction of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide(22a) (140 mg, 0.212 mmol) in ethanol (10 mL) using conc. HCl (0.177 mL,2.122 mmol) as reported in step 6 of Scheme 4 gave(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-p-tolylpyrrolidine-1,2-dicarboxamide(22b) (39 mg, 0.070 mmol, 33.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.60 (s, 1H), 8.27 (s, 1H), 8.07 (d, J=7.5 Hz, 1H), 7.87(t, J=1.7 Hz, 1H), 7.73-7.57 (m, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.40-7.34(m, 2H), 7.15-7.09 (m, 2H), 7.03 (d, J=8.3 Hz, 2H), 5.29 (d, J=4.3 Hz,1H), 4.49 (dd, J=9.1, 4.5 Hz, 1H), 4.33 (m, 1H), 3.66 (dd, J=10.1, 5.1Hz, 1H), 3.48 (dd, J=10.0, 3.9 Hz, 1H), 2.44-2.27 (m, 3H), 2.22 (m, 5H),1.98-1.84 (m, 1H), 1.10-0.93 (m, 2H), 0.72-0.54 (m, 1H), 0.40-0.26 (m,2H), −0.06 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −129.66; MS (ES+) 578.5(M+Na), (ES−) 554.6 (M−1), 590.5 (M+Cl); Optical rotation [α]_(D)=(+)92.5 [0.24, MeOH]; Analysis calculated for C₃₂H₃₄FN₅O₃.0.25H₂O: C,68.61; H, 6.21; N, 12.50. Found, 68.68; H, 6.26; N, 12.30; Opticalrotation [α]_(D)=(+) 90.0 [0.32, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-bromophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(23b) Step 1: Preparation of(2R,4R)-N1-(4-bromophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(23a)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(21b) (160 mg, 0.304 mmol) and 4-Bromophenyl isocyanate (72.2 mg, 0.365mmol) in tetrahydrofuran (10 mL) using reaction and workup conditions asreported in step 9 of Scheme 1 gave(2R,4R)-N1-(4-bromophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(23a) (192 mg, 0.265 mmol, 87% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.66 (s, 1H), 8.52 (s, 1H), 8.06 (dd, J=7.4, 2.3 Hz, 1H),7.79 (t, J=1.6 Hz, 1H), 7.71 (dt, J=7.5, 1.3 Hz, 1H), 7.59 (dt, J=8.2,1.6 Hz, 1H), 7.54-7.46 (m, 3H), 7.45-7.37 (m, 2H), 7.23-7.14 (m, 1H),7.11-7.03 (m, 1H), 5.50 (s, 1H), 5.33 (d, J=4.4 Hz, 1H), 4.51 (dd,J=9.0, 4.7 Hz, 1H), 4.41-4.27 (m, 1H), 3.68 (dd, J=10.1, 5.2 Hz, 1H),3.49 (dd, J=9.9, 3.8 Hz, 1H), 2.77-2.60 (m, 1H), 2.64-2.51 (m, 1H),2.47-2.24 (m, 1H), 1.97-1.78 (m, 1H), 1.13 (s, 10H), 0.98-0.77 (m, 1H),0.63 (m, 1H), 0.41-0.22 (m, 2H), −0.02-−0.17 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −128.38; MS: (ES+) 746.5, 748.5 (M+Na), (ES−) 722.5 (M−1),758.5, 760.4 (M+Cl); Optical rotation [α]_(D)=(−) 12.9 [0.155, MeOH].

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-bromophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(23b)

Reaction of(2R,4R)-N1-(4-bromophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(23a) (180 mg, 0.248 mmol) in ethanol (10 mL) using conc. HCl (0.207 mL,2.484 mmol) as reported in step 6 of Scheme 4 gave(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-bromophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(23b) (41 mg, 0.066 mmol, 26.6% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.50 (s, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.86(t, J=1.7 Hz, 1H), 7.67-7.59 (m, 2H), 7.53-7.45 (m, 3H), 7.44-7.37 (m,2H), 7.12 (d, J=8.9 Hz, 2H), 5.30 (d, J=4.7 Hz, 1H), 4.50 (dd, J=9.1,4.8 Hz, 1H), 4.41-4.28 (m, 1H), 3.68 (dd, J=10.2, 5.4 Hz, 1H), 3.47 (dd,J=9.8, 4.0 Hz, 1H), 2.40-2.14 (m, 5H), 2.01-1.79 (m, 1H), 1.13-0.88 (m,2H), 0.63 (m, 1H), 0.42-0.27 (m, 2H), −0.02-−0.12 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −129.26; MS (ES+) 642.4, 644.5 (M+Na); IR (KBr) 2229cm⁻¹; Optical rotation [α]_(D)=(+) 101.54 [0.325, MeOH]; Analysiscalculated for C₃₁H₃₁BrFN₅O₃.0.5H₂O: C, 59.15; H, 5.12; N, 11.12. Found:C, 59.11; H, 5.18; N, 10.95.

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(24b) Step 1: Preparation of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(24a)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(21b) (160 mg, 0.304 mmol) and 4-fluorophenyl isocyanate (0.041 mL,0.365 mmol) in tetrahydrofuran (10 mL) using reaction and workupconditions as reported in step 9 of Scheme 1 gave(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(24a) (138 mg, 0.208 mmol, 68.4% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.64 (d, J=7.0 Hz, 1H), 8.43 (s, 1H), 8.08 (dd, J=7.6,2.5 Hz, 1H), 7.91-7.75 (m, 1H), 7.71 (dt, J=7.4, 1.4 Hz, 1H), 7.59 (dt,J=8.2, 1.6 Hz, 1H), 7.50 (m, 3H), 7.12-7.01 (m, 3H), 5.50 (m, 1H), 5.32(d, J=4.5 Hz, 1H), 4.50 (dd, J=9.1, 4.5 Hz, 1H), 4.41-4.28 (m, 1H), 3.66(dd, J=10.0, 5.1 Hz, 1H), 3.49 (dd, J=10.2, 3.8 Hz, 1H), 2.74-2.51 (m,2H), 2.49-2.23 (m, 2H), 1.98-1.81 (m, 1H), 1.13 (d, J=2.2 Hz, 10H),0.98-0.76 (m, 1H), 0.70-0.52 (m, 1H), 0.38-0.27 (m, 2H), 0.01-−0.16 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −121.20, −128.61; MS: (ES+) 664.5(M+1), 686.5 (M+Na), (ES−) 662.5 (M−1), 698.5 (M+Cl); Optical rotation[α]_(D)=(−) 10.52 [0.095, MeOH].

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(24b)

Reaction of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(24a) (125 mg, 0.188 mmol) in ethanol (10 mL) using conc. HCl (0.157 mL,1.883 mmol) as reported in step 6 of Scheme 4 gave(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(24b) (35 mg, 0.063 mmol, 33.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.60 (s, 1H), 8.42 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.86(t, J=1.8 Hz, 1H), 7.63 (m, 2H), 7.55-7.41 (m, 3H), 7.18-7.06 (m, 2H),7.05 (d, J=7.0 Hz, 1H), 5.30 (d, J=4.7 Hz, 1H), 4.49 (dd, J=9.1, 4.6 Hz,1H), 4.43-4.22 (m, 1H), 3.67 (dd, J=10.1, 5.3 Hz, 1H), 3.58-3.31 (m,1H), 2.37-2.17 (m, 6H), 1.98-1.77 (m, 1H), 1.11-0.94 (m, 2H), 0.71-0.54(m, 1H), 0.40-0.26 (m, 2H), −0.03-−0.12 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −121.39, −129.49; MS (ES+) 582.5 (M+Na); Optical rotation[α]_(D)=(+) 85.93 [0.27, MeOH]

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide(25b) Step 1: Preparation of(2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide(25a)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(21b) (280 mg, 0.532 mmol) and 4-nitrophenyl isocyanate (105 mg, 0.638mmol) in tetrahydrofuran (10 mL) using reaction and workup conditions asreported in step 9 of Scheme 1 gave(2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide(25a) (353 mg, 0.511 mmol, 96% yield) as a light yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.72 (s, 1H), 9.07 (s, 1H), 8.19-8.10 (m, 2H), 8.02(d, J=7.1 Hz, 1H), 7.85-7.75 (m, 3H), 7.70 (m, 1H), 7.62-7.55 (m, 1H),7.50 (t, J=7.8 Hz, 1H), 7.19 (dd, J=10.5, 8.7 Hz, 1H), 7.15-7.02 (m,1H), 5.51 (s, 1H), 5.35 (s, 1H), 4.56 (dd, J=8.8, 5.1 Hz, 1H), 4.36 (m,1H), 3.75 (dd, J=10.1, 5.4 Hz, 1H), 3.52 (dd, J=9.9, 4.2 Hz, 1H),3.48-3.38 (m, 1H), 2.75-2.51 (m, 1H), 2.48-2.30 (m, 1H), 1.89 (m, 1H),1.13 (s, 9H), 1.11-1.01 (m, 1H), 0.90 (m, 1H), 0.61 (m, 1H), 0.38-0.30(m, 2H), −0.00-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.81; MS(ES+) 713.5 (M+Na), (ES−) 689.5 (M−1), 725.5 (M+Cl); Optical rotation[α]_(D)=(+) 18.66 [0.15, MeOH].

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide(25b)

Reaction of(2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide(25a) (100 mg, 0.145 mmol) in ethanol (10 mL) using conc. HCl (0.121 mL,1.448 mmol) as reported in step 6 of Scheme 4 gave(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide(25b) (61 mg, 0.104 mmol, 71.8% yield) as a light yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.66 (s, 1H), 9.05 (d, J=2.7 Hz, 1H), 8.15 (ddt,J=9.3, 4.3, 2.1 Hz, 2H), 7.99 (d, J=7.3 Hz, 1H), 7.89-7.75 (m, 3H),7.69-7.56 (m, 2H), 7.47 (ddd, J=8.0, 3.9, 2.3 Hz, 1H), 7.18-7.07 (m,2H), 5.32 (td, J=4.9, 4.2, 2.2 Hz, 1H), 4.63-4.45 (m, 1H), 4.41-4.25 (m,1H), 3.85-3.65 (m, 1H), 3.58-3.43 (m, 1H), 2.49-2.37 (m, 1H), 2.36-2.26(m, 1H), 2.29-2.13 (m, 3H), 1.89 (d, J=13.0 Hz, 1H), 1.12-0.92 (m, 2H),0.71-0.53 (m, 1H), 0.40-0.26 (m, 2H), −0.02-−0.15 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −128.42; MS (ES+) 609.5 (M+Na), (ES−) 585.5 (M−1), 621.4(M+Cl); Optical rotation [α]_(D)=(+) 124.90 [0.27, MeOH]; Analysiscalculated for C₃₁H₃₁FN₆O₅.0.5H₂O: C, 62.51; H, 5.42; N, 14.11. Found:C, 62.58; H, 5.43; N, 13.89.

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide(26b) Step 1: Preparation of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide(26a)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(21b) 160 mg, 0.304 mmol and 1-isocyanatonaphthalene (61.7 mg, 0.365mmol) in tetrahydrofuran (10 mL) using reaction and workup conditions asreported in step 9 of Scheme 1 gave(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide(26a) (196 mg, 0.282 mmol, 93% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.69 (s, 1H), 8.55 (s, 1H), 8.17 (dd, J=7.7, 2.4 Hz, 1H),8.04-7.95 (m, 1H), 7.91 (dd, J=8.2, 1.4 Hz, 1H), 7.79 (t, J=1.7 Hz, 1H),7.77-7.67 (m, 2H), 7.58 (m, 1H), 7.54-7.39 (m, 5H), 7.21 (dd, J=10.6,8.7 Hz, 1H), 7.07 (m, 1H), 5.47 (s, 1H), 5.38 (s, 1H), 4.56 (dd, J=9.3,3.9 Hz, 1H), 4.42 (s, 1H), 3.80 (dd, J=10.3, 4.9 Hz, 1H), 3.64 (dd,J=10.0, 3.1 Hz, 1H), 2.75-2.51 (m, 2H), 2.42 (m, 1H), 2.09-2.00 (m, 1H),1.12 (s, 10H), 0.99-0.79 (m, 1H), 0.70-0.54 (m, 1H), 0.41-0.26 (m, 2H),−0.02-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d6) δ −129.33; MS (ES+)718.5 (M+Na), (ES−) 694.6 (M−1), 730.5 (M+Cl); Optical rotation[α]_(D)=(−) 61.3 [0.075, MeOH].

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide(26b)

Reaction of(2R,4R)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide(26a) (160 mg, 0.230 mmol) in ethanol (10 mL) using conc. HCl 0.192 mL,2.299 mmol) as reported in step 6 of Scheme 4 gave(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(naphthalen-1-yl)pyrrolidine-1,2-dicarboxamide(26b) (30 mg, 0.051 mmol, 22.05% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.63 (s, 1H), 8.53 (s, 1H), 8.13 (d, J=7.1 Hz, 1H), 8.00(d, J=8.2 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.87 (t, J=1.7 Hz, 1H),7.77-7.69 (m, 1H), 7.66-7.62 (m, 1H), 7.51-7.40 (m, 5H), 7.20-7.07 (m,2H), 5.34 (s, 1H), 4.55 (dd, J=9.3, 4.0 Hz, 1H), 4.46-4.28 (m, 1H), 3.81(dd, J=10.3, 5.0 Hz, 1H), 3.68-3.55 (m, 1H), 2.48-2.35 (m, 2H), 2.30 (s,2H), 2.22 (t, J=8.1 Hz, 2H), 2.08-1.96 (m, 1H), 1.12-0.94 (m, 2H),0.71-0.55 (m, 1H), 0.39-0.28 (m, 2H), −0.03-−0.15 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −129.99; MS (ES+) 614.5 (M+Na), (ES−) 590.6 (M−1), 626.5(M+Cl); Optical rotation [α]_(D)=(+) 81.2 [0.165, MeOH]; Analysiscalculated for: C₃₅H₃₄FN₅O₃.0.5H₂O: C, 69.98; H, 5.87; N, 11.66. Found:C, 70.25; H, 5.99; N, 11.44.

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide(27b) Step 1: Preparation of(2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide(27a)

Reaction of(2R,4R)-N-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(21b) (160 mg, 0.304 mmol) and 1-isocyanato-4-(trifluoromethyl)benzene(0.043 mL, 0.304 mmol) in tetrahydrofuran (10 mL) using reaction andworkup conditions as reported in step 9 of Scheme 1 gave(2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide(27a) (161 mg, 0.226 mmol, 74.2% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.76 (s, 1H), 8.04 (d, J=7.3 Hz, 1H),7.89-7.62 (m, 4H), 7.60 (m, 2H), 7.50 (m, 1H), 7.25-7.11 (m, 1H), 7.04(m, 1H), 5.50 (d, J=5.7 Hz, 1H), 5.35 (d, J=4.1 Hz, 1H), 4.54 (dd,J=9.0, 4.7 Hz, 1H), 4.41-4.28 (m, 2H), 3.72 (m, 1H), 3.52 (m, 1H),2.75-2.54 (m, 1H), 2.48-2.24 (m, 1H), 1.99-1.80 (m, 1H), 1.13 (m, 10H),1.11-1.00 (m, 1H), 0.97-0.76 (m, 1H), 0.71-0.56 (m, 1H), 0.42-0.26 (m,2H), 0.00-−0.18 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d6) δ −59.80, −128.17;MS (ES+) 736.5 (M+Na), (ES−) 712.6 (M−1), 748.5 (M+Cl); Optical rotation[α]_(D)=(+) 14.19 [0.155, MeOH].

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide(27b)

Reaction of(2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide(27a) (150 mg, 0.210 mmol) in ethanol (10 mL) using conc. HCl (0.175 mL,2.101 mmol) as reported in step 6 of Scheme 4 gave(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-N1-(4-(trifluoromethyl)phenyl)pyrrolidine-1,2-dicarboxamide(27b) (50 mg, 0.082 mmol, 39.0% yield) as a white solid; ¹H NMR (300MHz, DMSO-d6) δ 9.63 (s, 1H), 8.74 (s, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.86(t, J=1.8 Hz, 1H), 7.74 (d, J=8.5 Hz, 2H), 7.61 (m, 4H), 7.46 (t, J=7.8Hz, 1H), 7.12 (d, J=8.0 Hz, 2H), 5.31 (d, J=4.7 Hz, 1H), 4.53 (dd,J=9.0, 4.9 Hz, 1H), 4.42-4.27 (m, 1H), 3.72 (dd, J=10.1, 5.3 Hz, 1H),3.57-3.45 (m, 1H), 2.42-2.15 (m, 5H), 1.97-1.77 (m, 1H), 1.09-0.92 (m,2H), 0.70-0.55 (m, 1H), 0.41-0.24 (m, 2H), −0.02-−0.14 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d6) δ −59.77, −128.84; MS(ES+) 632.5 (M+Na), (ES−) 608.4(M−1), 644.5 (M+Cl); Optical rotation [α]_(D)=(+) 94.00 [0.3, MeOH];Analysis calculated for C₃₂H₃₁F₄N₅O₃.0.5H₂O: C, 62.13; H, 5.21; N,11.32. Found: C, 62.54; H, 5.34; N, 11.15.

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-aminophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(28b) Step 1: Preparation of(2R,4R)-N1-(4-aminophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(28a)

Reduction of nitro to amine by hydrogenation of(2R,4R)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxy-N1-(4-nitrophenyl)pyrrolidine-1,2-dicarboxamide(25a) (200 mg, 0.290 mmol) in ethanol (20 mL), using palladium on carbon10% (30.8 mg, 0.029 mmol) as catalyst according to procedure reported instep 2 of Scheme 13 gave(2R,4R)-N1-(4-aminophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(28a) (160 mg, 0.242 mmol, 84% yield) as a light yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.15 (d,J=7.4 Hz, 1H), 7.98 (s, 1H), 7.79 (t, J=1.9 Hz, 1H), 7.70 (dd, J=7.2,1.5 Hz, 1H), 7.63-7.55 (m, 1H), 7.50 (td, J=7.8, 2.3 Hz, 1H), 7.19 (ddd,J=10.6, 8.6, 2.0 Hz, 1H), 7.11-7.01 (m, 3H), 6.46 (dd, J=8.8, 2.2 Hz,2H), 5.48 (d, J=1.8 Hz, 1H), 5.29 (dd, J=4.7, 2.0 Hz, 1H), 4.74 (s, 2H),4.46 (dd, J=9.3, 4.0 Hz, 1H), 4.41-4.26 (m, 1H), 3.59 (m, 1H), 3.53-3.41(m, 1H), 2.75-2.50 (m, 1H), 2.41-2.22 (m, 1H), 1.94 (d, J=13.4 Hz, 1H),1.21-1.03 (m, 10H), 0.98-0.79 (m, 1H), 0.72-0.53 (m, 1H), 0.44-0.28 (m,2H), −0.03-−0.11 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −129.01; MS (ES+)661.5 (M+1), 683.5 (M+Na), (ES−) 659.5 (M−1), 695.6 (M+Cl); Opticalrotation [α]_(D)=(−) 21.9 [0.155, MeOH].

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-aminophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(28b)

Reaction of(2R,4R)-N1-(4-aminophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(28a) (0.15 g, 0.227 mmol) in ethanol (10 mL) using conc. HCl (0.208 mL,2.497 mmol) as reported in step 6 of Scheme 4 gave(2R,4R)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-aminophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(28b) (65 mg, 0.117 mmol, 51.4% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.57 (d, J=1.8 Hz, 1H), 8.12 (dd, J=7.7, 2.1 Hz, 1H),7.97 (s, 1H), 7.87 (t, J=1.8 Hz, 1H), 7.67-7.58 (m, 2H), 7.46 (t, J=7.8Hz, 1H), 7.19-7.08 (m, 2H), 7.08-7.00 (m, 2H), 6.50-6.40 (m, 2H), 5.26(d, J=4.7 Hz, 1H), 4.75 (s, 2H), 4.45 (dd, J=9.2, 4.1 Hz, 1H), 4.38-4.23(m, 1H), 3.59 (dd, J=10.1, 4.9 Hz, 1H), 3.45 (dd, J=10.0, 3.3 Hz, 1H),2.41-2.27 (m, 3H), 2.23 (t, J=8.1 Hz, 2H), 2.00-1.86 (m, 1H), 1.02 (m,2H), 0.72-0.54 (m, 1H), 0.39-0.27 (m, 2H), −0.02-−0.14 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −130.17; MS (ES+) 579.5 (M+Na), (ES−) 555.5 (M−1),593.6 (M+Cl); Optical rotation [α]_(D)=(+) 100.8 [0.25, MeOH]; AnalysisCalculated for C₃₁H₃₃FN₆O₃.0.5H₂O: C, 65.83; H, 6.06; N, 14.86. Found:C, 65.67; H, 5.98; N, 14.58.

Preparation of(2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(29e) Step 1: Preparation of(R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (29a)

To a solution of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(14b) (51 g, 221 mmol) in dichloromethane (2023 mL) at 0° C. containingtrichloroisocyanuric acid (51.3 g, 221 mmol) was added TEMPO (1.723 g,11.03 mmol), stirred at 0° C. for 30 min and allowed to warm to roomtemperature overnight. The reaction mixture was diluted with water (100mL) stirred for 30 min and concentrated in vacuum to removedichloromethane. The reaction mixture was diluted with 200 mL ethylacetate, filtered through a plug of Celite. The filtrate was acidifiedwith 8 mL of 1M HCl. The ethyl acetate layer was separated washed withwater (4×200 mL), brine (100 mL), dried, filtered, and concentrated invacuum to afford(R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (29a) (38g, 166 mmol, 75% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ13.00 (s, 1H), 4.53 (m, 1H), 3.82 (dd, J=18.6, 10.6 Hz, 1H), 3.66 (dd,J=18.4, 4.4 Hz, 1H), 3.44 (s, 1H), 3.12 (m, 1H), 1.40 (s, 9H); MS (ES−)228.2 (M−1), 457.3 (2M−1).

Step 2: Preparation of(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylicacid (29b)

A solution of (R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylicacid (29a) (1.45 g, 6.33 mmol) in THF (20 mL) was added dropwise to a1.0M solution of phenylmagnesium bromide (17.40 mL, 17.40 mmol) at 0° C.The reaction mixture was stirred at 0° C. for 20 min, quenched withsaturated ammonium chloride (15 mL) and concentrated in vacuum to removeorganic solvents. The reaction mixture was partitioned between ethylacetate (50 mL) and 1M HCl (20 mL). The organic layer was separatedwashed with brine, dried, filtered and concentrated to a volume of 25 mLthe solution was diluted with stirring with hexanes (70 mL). The solidobtained was collected by filtration washed with hexanes, dried invacuum to yield(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylicacid (29b) (900 mg, 2.93 mmol, 46.3% yield) as a light brown solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.47 (s, 1H), 7.53 (d, J=7.7 Hz, 2H), 7.41 (t,J=7.5 Hz, 2H), 7.33 (q, J=7.1, 6.5 Hz, 1H), 5.59 (s, 1H), 4.47-4.29 (m,1H), 3.76-3.55 (m, 2H), 2.74-2.61 (m, 1H), 2.31 (dd, J=12.8, 6.7 Hz,1H), 1.56-1.40 (m, 9H); MS (ES+) 330.3 (M+Na), (ES−) 306.3 (M−1);Optical rotation [α]_(D)=(+) 38.43 [0.255, MeOH].

Step 3: Preparation of (2R,4S)-tert-butyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate(29c)

Reaction of(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylicacid (29b) (500 mg, 1.627 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(4e) (673 mg, 1.627 mmol) in tetrahydrofuran (75 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (402 mg, 1.627 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%) (2R,4S)-tert-butyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate(29c) (345 mg, 0.491 mmol, 30.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.78 (2s, 1H, rotamers), 8.40-7.98 (2m, 1H, rotamers),7.77 (m, 1H), 7.72 (m, 1H), 7.64 (m, 1H), 7.58-7.46 (m, 3H), 7.37 (m,2H), 7.33-6.99 (m, 4H), 6.00 (2s, 1H, rotamers), 5.48 (2s, 1H,rotamers), 4.66-4.30 (m, 1H), 3.82-3.53 (m, 2H), 2.80-2.55 (m, 2H),2.33-2.14 (m, 1H), 1.32 (2s, 9H, rotamers), 1.14 (2s, 10H, rotamers),1.00-0.75 (m, 1H), 0.71-0.52 (m, 1H), 0.44-0.26 (m, 2H), 0.01-−0.17 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.69, −129.87; MS (ES+) 725.5(M+Na), (ES−) 701.6 (M−1), 737.5 (M+Cl); Optical rotation [α]_(D)=(−)71.10 [0.09, MeOH].

Step 4: Preparation of(2R,4S)-N-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(29d)

Reaction of (2R,4S)-tert-butyl2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate(29c) (335 mg, 0.477 mmol) in methanolic HCl (2.383 mL, 7.15 mmol)followed by workup and purification as reported in step 6 of Scheme 4gave(2R,4S)-N-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(29d) (260 mg, 0.455 mmol, 95% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.56 (s, 1H), 10.26 (s, 1H), 9.45 (s, 3H), 8.78 (s, 1H),7.90 (m, 2H), 7.86 (m, 1H), 7.72-7.63 (m, 2H), 7.57-7.51 (m, 2H),7.49-7.24 (m, 5H), 5.88 (s, 1H), 4.72 (m, 1H), 3.60-3.41 (m, 3H), 2.79(t, J=12.4 Hz, 1H), 1.26-1.14 (m, 1H), 1.14-1.01 (m, 3H), 0.82-0.59 (m,1H), 0.48-0.32 (m, 2H), 0.11-−0.06 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ−123.49; MS (ES+) 521.5 (M+Na), (ES−) 533.5 (M+Cl); Optical rotation[α]_(D)=(−) 56.67 [0.18, MeOH].

Step 5: Preparation of(2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(29e)

Reaction of(2R,4S)-N-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(29d) (99 mg, 0.173 mmol) in tetrahydrofuran (20 mL) with phenyl5-chloropyridin-2-ylcarbamate (43.1 mg, 0.173 mmol) using sodiumbicarbonate (3.46 mL, 3.46 mmol) as base according to procedure reportedin step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel 12 g, eluting with 0-100% CMA-80 inchloroform)(2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(29e) (65 mg, 0.100 mmol, 57.5% yield) as an off white solid; 1H NMR(300 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.24 (s, 1H), 8.30 (dd, J=2.7, 0.8Hz, 1H), 8.11 (d, J=7.6 Hz, 1H), 7.91 (dd, J=9.1, 0.8 Hz, 1H), 7.87 (t,J=1.7 Hz, 1H), 7.81 (dd, J=9.0, 2.6 Hz, 1H), 7.68-7.61 (m, 2H), 7.54(dt, J=6.6, 1.3 Hz, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.42-7.34 (m, 2H),7.33-7.26 (m, 1H), 7.20-7.11 (m, 2H), 5.95 (s, 1H), 4.71 (d, J=8.5 Hz,1H), 4.02-3.96 (m, 1H), 3.90 (d, J=10.5 Hz, 1H), 2.68 (dd, J=13.2, 9.7Hz, 1H), 2.34 (s, 2H), 2.34-2.18 (m, 3H), 1.11-0.95 (m, 2H), 0.74-0.54(m, 1H), 0.39-0.29 (m, 2H), −0.01-−0.11 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −129.26; MS (ES+) 653.5 (M+1) 675.4, 677.5 (M+Na), (ES−)651.5, 653.7 (M−1), 689.5 (M+Cl); IR (KBr) 2229 cm¹; Optical rotation[α]_(D)=(+) 80 [0.295, MeOH].

Preparation of(2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(30a) and(2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-(4-chlorophenyl)ureido)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(30b)

Reaction of(2R,4S)-N-(5-((−)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(29d) (150 mg, 0.262 mmol) in dichloromethane (10 mL) with4-chlorophenyl isocyanate (1n) (0.034 mL, 0.262 mmol) and sodiumbicarbonate (5.25 mL, 5.25 mmol) according to procedure reported in step9 Scheme 1 gave after purification

-   -   1.        (2R,4S)-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide        (30a) (65 mg, 0.100 mmol, 38.0% yield) as a white solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 9.69 (s, 1H), 8.53 (s, 1H), 8.14 (d, J=7.5        Hz, 1H), 7.88 (t, J=1.7 Hz, 1H), 7.64 (m, 2H), 7.60-7.53 (m,        4H), 7.48 (d, J=7.8 Hz, 1H), 7.45-7.35 (m, 2H), 7.33-7.25 (m,        3H), 7.18-7.10 (m, 2H), 5.97 (s, 1H), 4.76-4.60 (m, 1H), 3.93        (d, J=10.2 Hz, 1H), 3.83 (d, J=10.1 Hz, 1H), 2.72 (dd, J=13.2,        9.5 Hz, 1H), 2.35-2.21 (m, 5H), 1.10-0.96 (m, 2H), 0.71-0.56 (m,        1H), 0.40-0.28 (m, 2H), −0.00-−0.11 (m, 2H); ¹⁹F NMR (282 MHz,        DMSO-d₆) δ −129.82; MS (ES+) 674.5, 677.5 (M+Na), (ES−) 650.5,        652.0 (M−1), 686.5, 688.6 (M+Cl); IR (KBr) 2229 cm-1; Optical        rotation [α]_(D)=(+) 87.5 [0.32,MeOH]; Analysis calculated for        C₃₇H₃₅ClFN₅O₃.0.25H₂O; C, 67.68; H, 5.45; N, 10.67. Found: C,        67.73; H, 5.53; N, 10.51.    -   2.        (2R,4S)-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-(4-chlorophenyl)ureido)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide        (30b) (68 mg, 0.084 mmol, 32.2% yield) as a white solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 9.73 (s, 1H), 8.85 (s, 1H), 8.55 (s, 1H),        8.20-8.10 (m, 1H), 7.80 (s, 1H), 7.67 (m, 2H), 7.58-7.49 (m,        5H), 7.43-7.18 (m, 10H), 7.14 (s, 1H), 7.08 (s, 1H), 5.96 (s,        1H), 4.68 (d, J=9.6 Hz, 1H), 3.93 (d, J=10.2 Hz, 1H), 3.83 (d,        J=10.1 Hz, 1H), 2.80-2.61 (m, 3H), 2.30 (d, J=13.6 Hz, 1H),        1.11-0.91 (m, 2H), 0.74-0.57 (m, 1H), 0.42-0.29 (m, 2H),        −0.01-−0.13 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −129.16; MS        (ES+) 827.5, 828.6 (M+Na), (ES−) 803.5, 805.4 (M−1), 839.5,        840.6 (M+Cl); IR (KBr) 2229 cm-1; Optical rotation [α]_(D)=(+)        52.0 [0.25, MeOH]; Analysis calculated for        C₄₄H₃₉Cl₂FN₆O₄.0.75H₂O: C, 64.51; H, 4.98; N, 10.26. Found: C,        64.49; H, 5.06; N, 9.99.

Preparation of(2R,4S)-N2-(5-((−)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(31i) Step-1: Preparation of(E)-3-cyclopropyl-1-(pyridin-2-yl)prop-2-en-1-one (31b)

To a stirred solution of 2-acetylpyridine (31a) (53 g, 438 mmol) inmethanol (636 mL) cooled to 0° C. was added cyclopropanecarboxaldehyde(52.8 mL, 700 mmol) and aqueous potassium hydroxide (1N solution, 88 mL,88 mmol). The reaction was allowed to warm to room temperatureovernight. The reaction was concentrated in vacuum to remove methanol.The crude residue was dissolved in ethyl acetate (500 mL) washed withwater (500 mL), brine (200 mL), dried, filtered and concentrated invacuum to afford (E)-3-cyclopropyl-1-(pyridin-2-yl)prop-2-en-1-one (31b)(80 g, 462 mmol, 106% yield) which was used as such for next step. Ananalytical sample was prepared by purification of crude residue by flashcolumn chromatography (silica gel, eluting with ethyl acetate in hexanes0 to 100%); ¹H NMR (300 MHz, DMSO-d₆) δ 8.80-8.68 (m, 1H), 8.07-7.98 (m,2H), 7.74-7.63 (m, 2H), 6.63 (dd, J=15.5, 10.4 Hz, 1H), 1.93-1.76 (m,1H), 1.08-0.98 (m, 2H), 0.84-0.71 (m, 2H).

Step-2: Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (31c)

To a stirred solution of(E)-3-cyclopropyl-1-(pyridin-2-yl)prop-2-en-1-one (31b) (80 g, 462 mmol)in acetonitrile (829 mL) was added tributylstanane (256 mL, 924 mmol)and heated at reflux for 9 h. The reaction was cooled to roomtemperature and layers were separated. The acetonitrile layer wasconcentrated in vacuum and residue obtained was purified by flash columnchromatography (silica gel, eluting with ethyl acetate in hexanes 0 to100%) to afford 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (31c) (17.2g, 98 mmol, 21.25% yield) as an oil ¹H NMR (300 MHz, DMSO-d₆) δ 8.94(dt, J=4.7, 1.5 Hz, 1H), 8.19 (m, 2H), 7.87 (m, 1H), 3.46 (td, J=7.2,2.0 Hz, 2H), 1.74 (qd, J=7.2, 2.1 Hz, 2H), 1.03-0.87 (m, 1H), 0.59 (m,2H), 0.30-0.20 (m, 2H).

Step-3: Preparation of(+)-N-(3-cyclopropyl-1-(pyridin-2-yl)propylidene)-2-methylpropane-2-sulfinamide(31d)

Reaction of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (31c) (15.2 g, 87mmol) in tetrahydrofuran (220 mL) with (S)-2-methylpropane-2-sulfinamide(12.62 g, 104 mmol) and tetraisopropoxytitanium (51.2 mL, 173 mmol)according to the procedure and workup reported in Step-3 of Scheme 1gave(+)-N-(3-cyclopropyl-1-(pyridin-2-yl)propylidene)-2-methylpropane-2-sulfinamide(31d) (11.65 g, 41.8 mmol, 48.2% yield) as an yellow oil; ¹H NMR (300MHz, DMSO-d₆) δ 8.70 (dt, J=4.7, 1.4 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H),7.94 (td, J=7.6, 1.7 Hz, 1H), 7.56 (ddd, J=7.5, 4.7, 1.4 Hz, 1H), 3.53(m, 1H), 3.41-3.35 (m, 1H), 1.49 (q, J=7.5 Hz, 2H), 1.25 (s, 9H),0.81-0.65 (m, 1H), 0.44-0.28 (m, 2H), 0.03 (m, 2H); MS (ES+) 279.3(M+1), 301.3 (M+Na); Optical rotation [α]_(D)=(+) 50.8 [2.64, MeOH].

Step-4: Preparation of(S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide(31e) and(S)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide(31f)

Reaction of(+)-N-(3-cyclopropyl-1-(pyridin-2-yl)propylidene)-2-methylpropane-2-sulfinamide(31d) (12.665 g, 45.5 mmol) in toluene (400 mL) with freshly preparedsolution of (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesiumbromide (1c) (142 mL, 114 mmol) according to the procedure reported instep 4 of Scheme 1 gave after purification by flash columnchromatography (silica gel, 120 g eluting with ethyl acetate in hexanes0 to 60 to 100%)

-   -   1.        (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide        (31e) (10 g, 25.7 mmol, 56.4% yield) as a white solid; ¹H NMR        (300 MHz, DMSO-d₆) δ 8.52 (dt, J=4.6, 1.5 Hz, 1H), 7.73 (td,        J=7.8, 1.9 Hz, 1H), 7.26 (ddd, J=7.5, 4.8, 1.0 Hz, 1H), 7.07        (dt, J=8.0, 1.1 Hz, 1H), 6.88 (dd, J=11.3, 8.5 Hz, 1H), 6.78        (dd, J=8.8, 2.4 Hz, 1H), 6.43 (ddd, J=8.6, 4.3, 2.3 Hz, 1H),        6.09 (s, 1H), 5.09 (s, 2H), 2.56 (m, 1H), 2.45 (m, 1H),        1.29-1.15 (m, 1H), 1.10 (s, 9H), 0.63-0.42 (m, 2H), 0.35-0.23        (m, 2H), −0.07 (m, 1H), −0.20 (m, 1H); ¹⁹F NMR (282 MHz,        DMSO-d₆) δ −137.14; MS: (ES+) 412.4 (M+Na), (ES−) 388.4 (M−1),        424.4 (M+Cl); Optical rotation [α]_(D)=(+) 136.36 [0.55, MeOH].    -   2.        (S)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide        (31f) (300 mg, 0.770 mmol, 1.693% yield) as a white solid; ¹H        NMR (300 MHz, DMSO-d₆) δ 8.53 (ddd, J=4.9, 1.9, 0.9 Hz, 1H),        7.71 (td, J=7.7, 1.8 Hz, 1H), 7.35-7.09 (m, 2H), 6.85 (dd,        J=11.3, 8.5 Hz, 1H), 6.71 (dd, J=8.8, 2.4 Hz, 1H), 6.41 (ddd,        J=8.5, 4.3, 2.4 Hz, 1H), 5.82 (s, 1H), 5.06 (s, 2H), 2.55 (d,        J=8.5 Hz, 2H), 1.13 (s, 9H), 1.08-0.96 (m, 1H), 0.81 (m, 1H),        0.61 (m, 1H), 0.38-0.29 (m, 2H), −0.10 (m, 2H); ¹⁹F NMR (282        MHz, DMSO-d₆) δ −137.42; MS (ES+) 390.4 (M+1), 412.4 (M+Na),        (ES−) 388.4 (M−1), 424.4 (M+Cl); Optical rotation [α]_(D)=(−)        3.28 [0.305, MeOH].

Step-5: Preparation of (2R,4S)-tert-butyl2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate(31g)

Reaction of(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylicacid (29b) (158 mg, 0.513 mmol),(S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide(31e) (200 mg, 0.513 mmol) in tetrahydrofuran (20 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (127 mg, 0.513 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%) (2R,4S)-tert-butyl2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate(31g) (130 mg, 0.191 mmol, 37.3% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.71 (2s, 1H, rotamers), 8.54 (2d, J=4.8 Hz, 1H,rotamers), 8.37-8.04 (m, 1H), 7.75 (m, 1H), 7.59-7.44 (m, 2H), 7.37 (m,2H), 7.33-7.23 (m, 1H), 7.23-6.94 (m, 2H), 6.14 (m, 1H), 5.95 (2s, 1H,rotamers), 4.44 (m, 1H), 3.67 (s, 2H), 2.79-2.51 (m, 5H), 2.23 (m, 1H),1.33 (2s, 9H, rotamers), 1.11 (s, 10H), 0.67-0.46 (m, 2H), 0.31 (m, 2H),0.01 (m, 1H), −0.18 (m, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.48,−129.79; MS (ES+) 679.6 (M+1), 701.6 (M+Na), (ES−) 677.7 (M−1), 713.6(M+Cl).

Step-6: Preparation of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(31h)

Reaction of (2R,4S)-tert-butyl2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate(31g) (125 mg, 0.184 mmol) in methanolic HCl (0.614 mL, 1.841 mmol)followed by workup and purification as reported in step 6 of Scheme 4gave(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(31h) (106 mg, 0.182 mmol, 99% yield) as a light brown solid; ¹H NMR(300 MHz, DMSO-d₆) δ 10.61 (s, 1H), 10.29 (s, 1H), 9.06 (s, 3H),8.96-8.78 (m, 1H), 8.74 (m, 1H), 8.10-8.02 (m, 1H), 7.96 (t, J=7.8 Hz,1H), 7.65-7.56 (m, 2H), 7.56-7.35 (m, 5H), 7.31 (s, 1H), 4.77 (m, 1H),3.94-3.50 (m, 5H), 2.97-2.75 (m, 1H), 1.39-1.20 (m, 1H), 1.16 (m, 2H),1.14-1.06 (m, 2H), 0.75 (m, 1H), 0.46 (m, 2H), 0.27-−0.13 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −123.51; MS (ES+) 475.5 (M+1), 497.5 (M+Na),(ES−) 473.6 (M−1), 509.5 (M+Cl).

Step-7: Preparation of(2R,4S)-N2-(5-((−)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(31i)

Reaction of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(31h) (50 mg, 0.086 mmol) in dichloromethane (10 mL) with 4-chlorophenylisocyanate (1n) (10.96 μL, 0.086 mmol) and sodium bicarbonate accordingto procedure reported in step 9 Scheme 1 gave after purification byflash column chromatography (silica gel, 12 g eluting with CMA 80 inchloroform)(2R,4S)-N2-(5-((−)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(31i) (36 mg, 0.057 mmol, 66.9% yield) as a off white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.64 (s, 1H), 8.53 (s, 1H), 8.48 (dt, J=4.5, 1.5 Hz,1H), 8.18 (dd, J=7.8, 2.2 Hz, 1H), 7.70 (td, J=7.7, 1.9 Hz, 1H),7.60-7.51 (m, 5H), 7.39 (t, J=7.5 Hz, 2H), 7.33-7.26 (m, 3H), 7.21-7.06(m, 3H), 5.98 (s, 1H), 4.68 (dd, J=9.6, 2.8 Hz, 1H), 3.93 (d, J=10.1 Hz,1H), 3.82 (d, J=10.1 Hz, 1H), 2.72 (dd, J=13.1, 9.7 Hz, 1H), 2.40-2.21(m, 5H), 1.04 (m, 2H), 0.70-0.55 (m, 1H), 0.40-0.26 (m, 2H), −0.01-−0.12(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −130.30; MS (ES+) 650.5, 651.4(M+Na), (ES−) 626.5 (M−1), 662.6, 664.5 (M+Cl); Optical rotation[α]_(D)=(−) 56.25 [0.16, MeOH].

Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(32a) and(2R,4S)-N1-(5-chloropyridin-2-yl)-N2-(5-(1-(3-(5-chloropyridin-2-yl)ureido)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(32b)

Reaction of(2R,4S)-N-(5-((−)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(31h) (50 mg, 0.086 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (21.29 mg, 0.086 mmol) using sodiumbicarbonate as base according to procedure reported in step 3 of Scheme13 gave after purification by flash column chromatography (silica gel 12g, eluting with 0-100% CMA-80 in chloroform)

-   -   1.        (2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide        (32a) (29 mg, 0.046 mmol, 53.8% yield) as off white solid; 1H        NMR (300 MHz, DMSO-d₆) δ 9.70 (s, 1H), 9.23 (s, 1H), 8.56-8.41        (m, 1H), 8.30 (d, J=2.7 Hz, 1H), 8.21-8.07 (m, 1H), 7.92 (d,        J=9.1 Hz, 1H), 7.81 (dd, J=9.0, 2.7 Hz, 1H), 7.70 (td, J=7.7,        1.9 Hz, 1H), 7.54 (d, J=7.8 Hz, 3H), 7.38 (t, J=7.5 Hz, 2H),        7.29 (m, 1H), 7.13 (m, 3H), 5.96 (s, 1H), 4.77-4.66 (m, 1H),        4.00 (d, J=10.5 Hz, 1H), 3.90 (d, J=10.4 Hz, 1H), 2.68 (dd,        J=13.2, 9.6 Hz, 1H), 2.38-2.32 (m, 3H), 2.34-2.22 (m, 2H),        1.12-0.94 (m, 2H), 0.70-0.54 (m, 1H), 0.40-0.25 (m, 2H),        0.00-−0.15 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −129.71; MS        (ES+) 629.5 (M+1) 652.5 (M+Na), (ES−) 627.5, 628.5 (M−1);        Optical rotation [α]_(D)=(+) 14.81 [0.27, MeOH].    -   2.        (2R,4S)-N1-(5-chloropyridin-2-yl)-N2-(5-(1-(3-(5-chloropyridin-2-yl)ureido)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide        (32b) (10 mg, 0.013 mmol, 14.90% yield) as off white solids; 1H        NMR (300 MHz, DMSO-d₆) δ 9.88 (s, 1H), 9.69 (s, 2H), 9.24 (s,        1H), 8.62 (d, J=4.9 Hz, 1H), 8.34 (d, J=2.6 Hz, 1H), 8.29 (d,        J=2.6 Hz, 1H), 8.25 (d, J=7.4 Hz, 1H), 7.92 (d, J=9.0 Hz, 1H),        7.85-7.67 (m, 3H), 7.53 (d, J=7.6 Hz, 2H), 7.37 (m, 3H), 7.26        (m, 3H), 7.14 (m, 2H), 5.92 (s, 1H), 4.71 (d, J=8.5 Hz, 1H),        4.00 (d, J=10.5 Hz, 1H), 3.90 (d, J=10.4 Hz, 1H), 2.76-2.64 (m,        1H), 2.67-2.54 (m, 2H), 2.40-2.20 (m, 1H), 1.13-0.93 (m, 2H),        0.70-0.53 (m, 1H), 0.30 (m, 2H), −0.07-−0.26 (m, 2H); ¹⁹F NMR        (282 MHz, DMSO-d₆) δ −129.58; MS (ES+) 783.6 (M+1) 805.5, 807.5        (M+Na).

Preparation of(2R,4S)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(33d) Step 1: Preparation of(3R,5R)-1-(4-chlorophenylcarbamoyl)-5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-ylmethanesulfonate (33a)

To a ice cold solution of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(4f) (110 mg, 0.162 mmol) in dichloromethane (10 mL) was addedtriethylamine (0.09 mL, 0.647 mmol), methanesulfonyl chloride (0.019 mL,0.243 mmol) and stirred at room temperature overnight. The reaction wasdiluted with dichloromethane (100 mL), washed with water (2×20 mL),brine (2×20 mL), dried, filtered and concentrated in vacuum to afford(3R,5R)-1-(4-chlorophenylcarbamoyl)-5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-ylmethanesulfonate (33a) (136 mg, 0.179 mmol, 111% yield) which was usedsuch for next step; ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.61 (s,1H), 7.87-7.75 (m, 2H), 7.70 (dt, J=7.4, 1.4 Hz, 1H), 7.64-7.44 (m, 4H),7.40-7.25 (m, 2H), 7.24-7.10 (m, 2H), 5.46 (s, 1H), 5.36 (d, J=6.6 Hz,1H), 4.01-3.91 (m, 1H), 3.86 (m, 1H), 3.35 (m, 2H), 3.18 (s, 3H),2.75-2.55 (m, 1H), 2.44-2.24 (m, 2H), 1.13 (s, 10H), 0.98-0.80 (m, 1H),0.63 (s, 1H), 0.39-0.30 (m, 2H), 0.01-−0.14 (m, 2H); MS (ES+) 780.5,782.4 (M+Na), (ES−) 792.5, 793.4 (M+Cl).

Step 2: Preparation of((2R,4S)-4-azido-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(33b)

To a stirred solution of3R,5R)-1-(4-chlorophenylcarbamoyl)-5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)pyrrolidin-3-ylmethanesulfonate (33a) (120 mg, 0.158 mmol) in DMF (10 mL) was addedsodium azide (41.1 mg, 0.633 mmol) and heated at 70° C. for 16 h.

The reaction was diluted with ethylacetate (100 mL), washed with water(2×25 mL), brine (25 mL), dried, filtered and concentrated in vacuum.The crude residue obtained was purified by flash column chromatography(silica gel, 12 g, eluting with CMA 80 In chloroform 0 to 100%) toafford((2R,4S)-4-azido-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(33b) (65 mg, 0.092 mmol, 58.2% yield) as a colorless solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.92 (s, 1H), 8.60 (s, 1H), 7.97 (d, J=7.1 Hz, 1H), 7.77(s, 1H), 7.74-7.67 (m, 1H), 7.62-7.44 (m, 3H), 7.31-7.25 (m, 2H),7.24-7.16 (m, 1H), 7.12 (m, 1H), 5.51 (s, 1H), 4.70 (t, J=7.5 Hz, 1H),4.45 (m, 1H), 3.77 (dd, J=11.0, 5.0 Hz, 1H), 3.62 (d, J=11.1 Hz, 1H),2.44 (m, 2H), 2.41-2.22 (m, 1H), 2.16 (m, 1H), 1.12 (s, 11H), 0.97-0.80(m, 1H), 0.70-0.53 (m, 1H), 0.39-0.27 (m, 2H), −0.01-−0.14 (m, 2H); 19FNMR (282 MHz, DMSO-d₆) δ −127.00; MS (ES+) 727.5, 729.5 (M+Na), (ES−)739.5 (M+Cl); Optical rotation [α]_(D)=(+) 62.25 [0.71, MeOH].

Step 3: Preparation of(2R,4S)-4-amino-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(33c)

Hydrogenation of((2R,4S)-4-azido-N1-(4-chlorophenyl)-N2-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(33b) (34 mg, 0.050 mmol) in ethanol (10 mL), using palladium on carbon10% (9.05 mg, 8.51 μmol) as catalyst for 3 h according to procedurereported in step 2 of Scheme 13 gave(2R,4S)-4-amino-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(33c) (34 mg, 0.050 mmol, 58.8% yield) as an off white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.81 (s, 1H), 8.43 (s, 1H), 7.91 (d, J=7.4 Hz, 1H),7.78 (d, J=2.1 Hz, 1H), 7.75-7.68 (m, 1H), 7.64-7.44 (m, 4H), 7.35-7.24(m, 2H), 7.23-7.06 (m, 1H), 5.51 (s, 1H), 4.65 (m, 1H), 3.81-3.70 (m,1H), 3.69-3.55 (m, 1H), 3.23-3.10 (m, 1H), 2.80-2.40 (m, 4H), 2.06-1.73(m, 3H), 1.12 (s, 10H), 0.99-0.78 (m, 1H), 0.71-0.54 (m, 1H), 0.43-0.25(m, 2H), −0.00-−0.14 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −126.77; MS(ES+) 701.6, 703.5 (M+Na), (ES−) 713.5, 715.6 (M+Cl); Optical rotation[α]_(D)=(−) 5.07 [0.355, MeOH].

Step 4: Preparation of(2R,4S)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(33d)

Reaction of(2R,4S)-4-amino-N1-(4-chlorophenyl)-N2-(5-((−)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)pyrrolidine-1,2-dicarboxamide(33c) (32 mg, 0.047 mmol) in ethanol (5 mL) using conc. HCl (0.039 mL,0.471 mmol) as reported in step 6 of Scheme 4 gave after purification byflash column chromatography (silica gel, eluting with CMA-80 inchloroform 0 to 100%)(2R,4S)-4-amino-N2-(5-((+)-1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)pyrrolidine-1,2-dicarboxamide(33d) (10 mg, 0.017 mmol, 36.9% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.76 (s, 1H), 8.44 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.86(d, J=1.8 Hz, 1H), 7.69-7.40 (m, 4H), 7.30-7.25 (m, 2H), 7.13 (d, J=7.8Hz, 2H), 4.64 (dd, J=8.3, 4.4 Hz, 1H), 3.74 (dd, J=9.4, 6.3 Hz, 1H),3.62 (p, J=6.6 Hz, 1H), 3.17 (dd, J=9.4, 5.8 Hz, 1H), 2.43-2.31 (m, 5H),2.22 (t, J=8.0 Hz, 2H), 2.10-1.87 (m, 2H), 1.11-0.91 (m, 2H), 0.71-0.54(m, 1H), 0.40-0.26 (m, 2H), −0.00-−0.15 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −127.63; MS (ES+) 597.4, 599.8 (M+Na), (ES−) 609.5, 610.4(M+Cl); Optical rotation [α]_(D)=(+) 136.0 [0.05, MeOH].

Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide(34d) Step-1: Preparation of(2R,4S)-1-(tert-butoxycarbonyl)-4-methoxy-4-phenylpyrrolidine-2-carboxylicacid (34a)

To a suspension of sodium hydride (60% dispersion in oil) (0.781 g,19.52 mmol) in tetrahydrofuran (40 mL) at −10° C. was added(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylicacid (29b) (1 g, 3.25 mmol), followed by the addition after 30 min ofdimethyl sulfate (0.311 mL, 3.25 mmol). The reaction mixture was allowedto warm to room temperature stirred for 16 h and quenched with saturatedaqueous ammonium chloride. THF was removed under vacuum and the residueobtained was basified and washed with ether. The aqueous layer wasacidified and extracted with ethyl acetate (2×100 mL). the combinedethyl acetate layer was washed with water (50 mL), brine (50 mL), dried,filtered and concentrated in vacuum to afford(2R,4S)-1-(tert-butoxycarbonyl)-4-methoxy-4-phenylpyrrolidine-2-carboxylicacid (34a) (673 mg, 2.094 mmol, 64.4% yield) as light brown solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.49 (s, 1H), 7.52-7.15 (m, 5H), 4.26 (m, 1H),3.82-3.65 (m, 1H), 3.53 (dd, J=13.4, 11.3 Hz, 1H), 2.82 (2s, 3H,rotamers), 2.67-2.55 (m, 2H), 1.38 (2S, 9H, rotamers); MS (ES+) 344.3(M+Na), (ES−) 320.3 (M−1); Optical rotation [α]_(D)=(+) 44.0 [0.25,MeOH].

Step-2: Preparation of(2R,4S)-tert-butyl-2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-phenylpyrrolidine-1-carboxylate(34b)

Reaction of(2R,4S)-1-(tert-butoxycarbonyl)-4-methoxy-4-phenylpyrrolidine-2-carboxylicacid (34a) (111 mg, 0.347 mmol),(S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide(31e) (86 mg, 0.347 mmol) in tetrahydrofuran (10 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (127 mg, 0.513 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%)(2R,4S)-tert-butyl-2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-phenylpyrrolidine-1-carboxylate(34b) (141 mg, 0.203 mmol, 58.7% yield) as a solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.66 (2s, 1H, rotamers), 8.73 (d, J=4.8 Hz, 1H), 8.36-8.12(m, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.60 (m, 4H), 7.52-7.19 (m, 4H), 6.34(s, 1H), 4.57 (m, 1H), 3.96 (s, 2H), 3.02 (2s, 3H, rotamers), 2.95-2.73(m, 3H), 2.74-2.53 (m, 2H), 1.52 (2s, 9H, rotamers), 1.31 (s, 9H),1.24-0.94 (m, 1H), 0.88-0.66 (m, 2H), 0.57-0.43 (m, 2H), 0.30-−0.06 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.09, −129.22 (rotamers); MS (ES+)693.7 (M+1), 715.7 (M+Na), (ES−) 691.7 (M−1), 727.7 (M+Cl); Opticalrotation [α]_(D)=(+) 122.60 [0.075, MeOH].

Step-3: Preparation of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide(34c)

Reaction of(2R,4S)-tert-butyl-2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-phenylpyrrolidine-1-carboxylate(34b) (131 mg, 0.189 mmol) in methanolic HCl (1.260 mL, 3.78 mmol)followed by workup and purification as reported in step 6 of Scheme 4gave(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide(34c) (125 mg, 0.209 mmol, 111% yield) as a hydrochloride salt which wasused directly as such in next step; MS (ES+) 511.5 (M+Na), (ES−) 523.5(M+Cl).

Step-4: Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide(34d)

Reaction of(2R,4S)-N-(5-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide(34c) (44 mg, 0.074 mmol) in dichloromethane (10 mL) with 4-chlorophenylisocyanate (1n) (9.42 μL, 0.074 mmol) and sodium bicarbonate accordingto procedure reported in step 9 Scheme 1 gave after purification byflash column chromatography (silica gel, 12 g eluting with CMA 80 inchloroform)(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide(34d) (36 mg, 0.056 mmol, 76% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.41 (s, 1H), 8.55 (s, 1H), 8.47 (m, 1H), 8.00-7.90 (m, 1H),7.69 (d, J=1.9 Hz, 1H), 7.62-7.50 (m, 3H), 7.45 (d, J=5.0 Hz, 3H),7.41-7.35 (m, 1H), 7.33-7.25 (m, 2H), 7.25-7.18 (m, 1H), 7.18-7.05 (m,2H), 4.62 (t, J=6.0 Hz, 1H), 4.11 (d, J=10.4 Hz, 1H), 3.79 (d, J=10.5Hz, 1H), 2.85 (s, 3H), 2.74-2.57 (m, 2H), 2.44-2.19 (m, 5H), 1.12-0.89(m, 2H), 0.72-0.51 (m, 1H), 0.42-0.24 (m, 2H), −0.02-−0.14 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −129.42; MS (ES+) 664.5, 665.6 (M+Na), (ES−)676.5 (M+Cl); Optical rotation [α]_(D)=(+) 89.0 [0.155, MeOH].

Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide

Reaction of(2R,4S)-N-(5-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide(34c) (50 mg, 0.084 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (20.79 mg, 0.084 mmol) using sodiumbicarbonate as base according to procedure reported in step 3 of Scheme13 gave after purification by flash column chromatography (silica gel 12g, eluting with 0-100% CMA-80 in chloroform)(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide(35a) (36 mg, 0.056 mmol, 66.9% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.41 (s, 1H), 9.21 (s, 1H), 8.47 (dd, J=4.8, 1.9 Hz,1H), 8.31 (d, J=2.6 Hz, 1H), 7.92 (m, 2H), 7.82 (dd, J=9.0, 2.7 Hz, 1H),7.69 (td, J=7.7, 1.9 Hz, 1H), 7.54 (dt, J=8.1, 1.1 Hz, 1H), 7.43 (d,J=4.0 Hz, 4H), 7.37 (m, 1H), 7.22 (m, 1H), 7.19-7.04 (m, 2H), 4.64 (t,J=6.2 Hz, 1H), 4.24 (d, J=10.8 Hz, 1H), 3.89 (d, J=10.9 Hz, 1H), 2.84(s, 3H), 2.61 (d, J=6.4 Hz, 2H), 2.43-2.24 (m, 4H), 1.12-0.95 (m, 2H),0.68-0.53 (m, 1H), 0.38-0.26 (m, 2H), −0.02-−0.14 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −128.95; MS (ES+) 665.5 (M+Na), (ES−) 641.6, 642.3(M−1); Optical rotation [α]_(D)=(+) 85.30 [0.075, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(36d) Step-1: Preparation of(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(36a)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(14b) (6 g, 26 mmol) with NaH (6.24 g, 156 mmol; 60% suspension in oil)in THF (300 mL) and Dimethyl Sulfate (3.9 g, 31 mmol) according to theprocedure reported in step 1 of Scheme 34 gave(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(36a) (5.82 g, 91%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 4.14(td, J=8.9, 3.7 Hz, 1H), 3.98-3.85 (m, 1H), 3.52 (m, 1H), 3.27-3.11 (m,4H), 2.33 (m, 1H), 2.00 (dt, J=13.3, 3.8 Hz, 1H), 1.37 (2s, 9H); MS(ES+) 268.4 (M+Na), MS (ES−) 244.3 (M−1), 280.3 (M+Cl); Optical rotation[α]_(D)=(+) 45.28 [0.265, MeOH].

Step-2: Preparation of (2R,4R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(36b)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(36a) (95 mg, 0.388 mmol),(S)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide(31f) (151 mg, 0.388 mmol) in tetrahydrofuran (25 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (96 mg, 0.388 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel, elutingwith CMA 80 in chloroform 0 to 100%) (2R,4R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(36b) (135 mg, 0.219 mmol, 56.5% yield) as a colorless solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.43 (2s, 1H, rotamers), 8.61-8.45 (m, 1H),7.89-7.66 (m, 2H), 7.33-7.23 (m, 2H), 7.15 (t, J=9.6 Hz, 1H), 7.06 (s,1H), 5.91 (2s, 1H, rotamers), 4.39-4.17 (m, 1H), 4.01-3.91 (m, 1H), 3.56(dd, J=11.0, 5.2 Hz, 1H), 3.21 (2s, 3H, rotamers), 2.70-2.52 (m, 2H),2.50-2.37 (m, 1H), 2.16-1.86 (m, 1H), 1.34 (2s, 9H, rotamers), 1.14 (s,10H), 1.11-0.94 (m, 1H), 0.97-0.79 (m, 1H), 0.71-0.54 (m, 1H), 0.42-0.26(m, 2H), −0.01-−0.16 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.64,−128.92 rotamers; MS (ES+) 639.5 (M+Na), (ES−) 615.6 (M−1); Opticalrotation [α]_(D)=(+) 11.42 [0.07, MeOH].

Step-3: Preparation of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(36c)

Reaction of (2R,4R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(36b) (120 mg, 0.195 mmol) in 3N methanolic HCl (0.973 mL, 2.92 mmol)followed by workup and purification as reported in step 6 of Scheme 4gave(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(36c) (100 mg, 0.192 mmol, 98% yield) hydrochloride salt which was usedas such for next step; MS: (ES+) 413.5 (M+1), 435.5 (M+Na), (ES−) 447.5(M+Cl).

Step-4: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(36d)

Reaction of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(36c) (95 mg, 0.182 mmol) in tetrahydrofuran (25 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (40.7 mg, 0.164 mmol) using sodiumbicarbonate (306 mg, 3.64 mmol) as base according to procedure reportedin step 3 of Scheme 13 gave after purification by flash columnchromatography(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(36d) (30 mg, 0.053 mmol, 29.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.42 (s, 1H), 9.14 (s, 1H), 8.53-8.42 (m, 1H), 8.30 (d,J=2.6 Hz, 1H), 7.91 (dd, J=9.8, 2.5 Hz, 2H), 7.81 (dd, J=9.1, 2.6 Hz,1H), 7.69 (td, J=7.7, 1.9 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.17 (m, 2H),7.08 (m, 1H), 4.57 (dd, J=9.1, 3.9 Hz, 1H), 4.12-3.98 (m, 1H), 3.81-3.61(m, 2H), 3.22 (s, 3H), 2.45-2.23 (m, 5H), 2.10 (m, 1H), 1.11-0.93 (m,2H), 0.69-0.53 (m, 1H), 0.39-0.23 (m, 2H), −0.05-−0.17 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −128.86; MS (ES+) 567.4, 569.4 (M+1), (ES−) 565.4,567.4 (M−1); Optical rotation [α]_(D)=(+) 70.7 [0.065, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(37d) Step-1: Preparation of benzyl(2R,4R)-2-((5-((+)-1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)carbamoyl)-4-methoxypyrrolidine-1-carboxylate(37a)

Reaction of(2R,4R)-1-(benzyloxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(15b) (0.17 g, 0.6 mmol),(S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide(31e) (0.2 g, 0.5 mmol) in tetrahydrofuran (5 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.15 g, 0.6 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography benzyl(2R,4R)-2-((5-((+)-1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)carbamoyl)-4-methoxypyrrolidine-1-carboxylate(37a) (0.29 g, 86%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.54(2s, 1H, rotamers), 8.58-8.50 (m, 1H), 7.97 (dd, J=7.6, 2.3 Hz, 1H),7.74 (t, J=7.9 Hz, 1H), 7.37 (s, 2H), 7.31-6.99 (m, 7H), 6.16 (s, 1H),5.16-4.91 (m, 2H), 4.51-4.34 (m, 1H), 4.05-3.91 (m, 1H), 3.74-3.58 (m,1H), 3.47-3.37 (m, 1H), 3.19 (d, J=5.3 Hz, 3H), 2.58 (m, 2H), 1.09 (m,9H, rotamers), 0.64-0.47 (m, 3H), 0.38-0.24 (m, 2H), −0.10-−0.25 (m,2H); MS (ES+) 651.6 (M+1), 673.5 (M+Na), MS (ES−) 685.6 (M+Cl); Opticalrotation [α]_(D)=(+) 131.3 [0.23, MeOH].

Step 2: Preparation of(2R,4R)-N-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(37b)

Debenzylation by hydrogenation of benzyl(2R,4R)-2-((5-((+)-1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)carbamoyl)-4-methoxypyrrolidine-1-carboxylate(37a) (0.28 g, 0.43 mmol) in ethanol (20 mL), using palladium on carbon10% as catalyst according to procedure reported in step 2 of Scheme 13gave(2R,4R)-N-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(37b) (0.21 g, 95% yield) as a gummy solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.09 (s, 1H), 8.58-8.49 (m, 1H), 8.32 (dd, J=7.8, 2.3 Hz, 1H), 7.74(td, J=7.8, 1.8 Hz, 1H), 7.31-7.14 (m, 2H), 7.11 (d, J=8.1 Hz, 2H),7.04-6.96 (m, 1H), 6.14 (s, 1H), 3.91-3.75 (m, 1H), 3.74 (d, J=7.2 Hz,1H), 3.04-2.98 (m, 1H), 2.90 (d, J=10.7 Hz, 1H), 2.66-2.54 (m, 5H),2.18-1.95 (m, 2H), 1.08 (s, 9H), 0.68-0.46 (m, 3H), 0.31 (m, 2H),−0.10-−0.25 (m, 2H); MS (ES+) 516.5 (M+1), 539.5 (M+Na), MS (ES−) 515.5(M−1).

Step 3: Preparation of(2R,4R)-N2-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(37c)

Reaction of(2R,4R)-N-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(37b) (0.1 g, 0.19 mmol) in THF (5 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (0.06 g, 0.23 mmol) using TEA (50μL) as base according to procedure reported in step 3 of Scheme 13 gaveafter purification by flash column chromatography(2R,4R)-N2-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(37c) (0.11 g, 84%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.50(s, 1H), 9.15 (s, 1H), 8.53 (dd, J=4.9, 1.8, Hz, 1H), 8.29 (d, J=2.6 Hz,1H), 7.96 (dd, J=7.6, 2.3 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.81 (dd,J=9.0, 2.6 Hz, 1H), 7.73 (td, J=7.8, 1.8 Hz, 1H), 7.26 (m, 1H),7.22-7.07 (m, 2H), 7.10-6.99 (m, 1H), 6.14 (s, 1H), 4.58 (dd, J=9.1, 3.9Hz, 1H), 4.03 (d, J=4.3 Hz, 1H), 3.72 (m, 2H), 3.21 (s, 3H), 2.63-2.52(m, 2H), 2.45-2.27 (m, 1H), 2.08 (m, 1H), 1.09 (s, 9H), 0.90-0.78 (m,2H), 0.64-0.46 (m, 1H), 0.36-0.23 (m, 2H), −0.19 (m, 2H); MS (ES+) 671.5(M+1), 693.5 (M+Na), MS (ES−) 669.5 (M−1), 705.5 (M+Cl).

Step 4: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(37d)

Reaction of (2R,4R)-N2-(5-(1-(((S)-tert-butylsulfinyl)amino)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(37c) (0.1 g, 0.15 mmol) in ethanol (5 mL) using conc. HCl (0.12 mL) asreported in step 6 of Scheme 4 gave after purification by flash columnchromatography(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(37d) (50 mg, 60% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.40 (d, J=1.4 Hz, 1H), 9.13 (s, 1H), 8.47 (ddd, J=4.9, 1.8, 0.9 Hz,1H), 8.30 (dd, J=2.6, 0.8 Hz, 1H), 7.90 (dd, J=8.2, 1.5 Hz, 2H), 7.81(dd, J=9.0, 2.6 Hz, 1H), 7.69 (td, J=7.7, 1.9 Hz, 1H), 7.53 (dt, J=8.1,1.1 Hz, 1H), 7.23-7.03 (m, 3H), 4.56 (dd, J=9.2, 3.9 Hz, 1H), 4.11-3.96(m, 1H), 3.81-3.64 (m, 2H), 3.21 (s, 3H), 2.43-2.20 (m, 4H), 2.09 (m,1H), 1.02 (m, 2H), 0.71-0.54 (m, 1H), 0.40-0.30 (m, 2H), −0.08 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.01; MS (ES+) 567.5 (M+1), (ES−) 603.5(M+Cl); Optical rotation [α]_(D)=(+) 70.7 [0.065, MeOH].

Preparation of(2R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethyl-4-hydroxypyrrolidine-1,2-dicarboxamide(38d) Step 1: Preparation of(2R)-1-(tert-butoxycarbonyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxylicacid (38a)

Reaction of (R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylicacid (29a) (0.502 g, 2.19 mmol) in THF (20 mL) with 1.0M solution ofethylmagnesiumbromide (6.02 mL, 6.02 mmol) using the reaction and workupconditions as reported in step 2 of Scheme 29 gave(2R)-1-(tert-butoxycarbonyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxylicacid (38a) (330 mg, 1.273 mmol, 58.1% yield) as an oil which was used assuch for next step; MS (ES+) 282.4 (M+Na), 541.6 (2M+Na), (ES−) 258.3(M−1), 517.6 (2M−1).

Step 2: Preparation of (2R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethyl-4-hydroxypyrrolidine-1-carboxylate(38b)

Reaction of(2R)-1-(tert-butoxycarbonyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxylicacid (38a) (300 mg, 1.157 mmol),(S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide(31e) (451 mg, 1.157 mmol) in tetrahydrofuran (25 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (402 mg, 1.627 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (2R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethyl-4-hydroxypyrrolidine-1-carboxylate(38b) (97 mg, 0.154 mmol, 13.29% yield) as a white solid; 1H NMR (300MHz, DMSO-d₆) δ 9.68 (2s, 1H, rotamers), 8.69-8.46 (m, 1H), 8.11 (2dd,1H, rotamers), 7.74 (m, 1H), 7.41-6.95 (m, 3H), 6.14 (d, J=6.5 Hz, 1H),5.08 (2s, 1H, rotamers), 4.41-4.21 (m, 1H), 3.30-3.17 (m, 1H), 2.67-2.54(m, 4H), 2.32-2.11 (m, 1H), 1.98-1.80 (m, 1H), 1.52 (m, 2H), 1.31 (2s,9H, rotamers), 1.10 (s, 9H), 0.88 (t, J=7.4 Hz, 3H), 0.57 (m, 3H),0.38-0.26 (m, 2H), 0.05-−0.28 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ−128.40, −129.65 rotamers; MS (ES+) 631.7 (M+1), 653.7 (M+Na), (ES−)629.7 (M−1), 665.7 (M+Cl); Optical rotation [α]_(D)=(+) 100.0 [0.07,MeOH].

Step 3: Preparation of(2R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxamide(38c)

Reaction of (2R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethyl-4-hydroxypyrrolidine-1-carboxylate(38b) (87 mg, 0.138 mmol) in methanol (20 mL) using 3N methanolic HCl(0.919 mL, 2.76 mmol) using the reaction and workup conditions asreported in step 6 of Scheme 4 gave(2R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxamide(38c) (69 mg, 0.138 mmol, 100% yield) as a hydrochloride salt, which wasused as such in next step without any further purification; MS (ES+)449.4 (M+Na), (ES−) 461.2 (M+Cl).

Step 4: Preparation of(2R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethyl-4-hydroxypyrrolidine-1,2-dicarboxamide(38d)

Reaction of(2R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-ethyl-4-hydroxypyrrolidine-2-carboxamide(38c) (65 mg, 0.130 mmol) in tetrahydrofuran (25 mL) with phenyl5-chloropyridin-2-ylcarbamate (29.1 mg, 0.117 mmol) using sodiumbicarbonate as base according to procedure reported in step 3 of Scheme13 gave after purification by flash column chromatography (silica gel 12g, eluting with 0-100% CMA-80 in chloroform)(2R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethyl-4-hydroxypyrrolidine-1,2-dicarboxamide(38d) (28 mg, 0.048 mmol, 37.0% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.68 (s, 1H), 9.13 (s, 1H), 8.47 (dd, J=4.7, 1.9 Hz,1H), 8.29 (d, J=2.6 Hz, 1H), 8.08 (dd, J=7.8, 2.3 Hz, 1H), 7.89 (d,J=9.1 Hz, 1H), 7.80 (dd, J=9.0, 2.6 Hz, 1H), 7.70 (m, 1H), 7.53 (m, 1H),7.25-7.03 (m, 3H), 5.77 (s, 1H), 5.11 (s, 1H), 4.63-4.45 (m, 1H), 3.64(d, J=10.3 Hz, 1H), 3.48 (d, J=10.4 Hz, 1H), 2.42-2.15 (m, 4H),2.01-1.89 (m, 1H), 1.56 (q, J=7.4 Hz, 2H), 1.12-0.97 (m, 2H), 0.92 (t,J=7.3 Hz, 3H), 0.71-0.52 (m, 1H), 0.40-0.26 (m, 2H), −0.02-−0.14 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d6) δ −129.61; MS (ES+) 581.4 (M+1), 604.5,606.4 (M+Na), (ES−) 579.4, 581.5 (M−1), 615.5, 616.5 (M+Cl); Opticalrotation [α]_(D)=(+) 67.37 [0.19, MeOH].

Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(39h) Step-1 Preparation of(E)-3-cyclopropyl-1-(pyridin-4-yl)prop-2-en-1-one (39b)

Reaction of 1-(pyridin-4-yl)ethanone (39a) (1.516 mL, 13.27 mmol) inmethanol (100 mL) with cyclopropanecarboxaldehyde (1.5 mL, 19.90 mmol)and aqueous potassium hydroxide (1N, 2.65 mL, 2.65 mmol) using thereaction and workup procedure as reported in Scheme 31 step 1 gave(E)-3-cyclopropyl-1-(pyridin-4-yl)prop-2-en-1-one (39b) (479 mg,20.85%); ¹H NMR (300 MHz, DMSO-d₆) δ 8.89-8.59 (m, 2H), 7.91-7.71 (m,2H), 7.19 (d, J=15.1 Hz, 1H), 6.58 (dd, J=15.1, 10.4 Hz, 1H), 1.88-1.71(m, 1H), 1.10-0.96 (m, 2H), 0.87-0.72 (m, 2H).

Step-2: Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (39c)

Reaction of (E)-3-cyclopropyl-1-(pyridin-4-yl)prop-2-en-1-one (39b)(18.35 g, 106 mmol) in acetonitrile (180 mL) and tributylstannane (60.0mL, 216 mmol) using the procedure reported in step 2 of Scheme 31 gaveafter purification by flash column chromatography (silica gel, elutingwith 0-30% ethyl acetate in hexane)3-cyclopropyl-1-(pyridin-4-yl)propan-1-one (39c) (3.028 g, 15%) as anoil; ¹H NMR (300 MHz, DMSO-d₆) δ 3.14 (t, J=7.2 Hz, 2H), 1.52 (q, J=7.1Hz, 2H), 0.75 (dddd, J=12.0, 8.1, 7.0, 2.8 Hz, 1H), 0.47-0.28 (m, 2H),0.14-0.02 (m, 2H).

Step-3: Preparation of(−)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(39d)

Compound (39d) was prepared from3-cyclopropyl-1-(pyridin-4-yl)propan-1-one (39c) (1.8 g, 10.27 mmol) and(R)-2-methylpropane-2-sulfinamide (1.566 g, 12.84 mmol) using procedureas reported in step 3 of scheme 31 to afford(−)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(39d) (1.838 g, 6.57 mmol, 63.9% yield) as a yellow syrup; ¹H NMR (300MHz, DMSO-d₆) δ 8.76-8.69 (m, 2H), 7.80-7.73 (m, 2H), 3.49-3.15 (m, 2H),1.45 (q, J=7.4 Hz, 2H), 1.24 (s, 9H), 0.84-0.65 (m, 1H), 0.43-0.30 (m,2H), 0.10-−0.03 (m, 2H); MS (ES+) 301.3, (M+Na); (ES−) 277.3 (M−1);Optical Rotation [α]_(D)=(−) 27.61 [0.355, MeOH].

Step-4: Preparation of(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e)

Compound (39e) was prepared from(−)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(39d) (1.7 g, 6.11 mmol), using procedure as reported in step 4 ofscheme 31 to afford(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (1.443 g, 3.7 mmol, 60.7% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.77-8.68 (m, 2H), 7.62-7.53 (m, 2H), 7.15 (dd, J=11.3,8.5 Hz, 1H), 7.00-6.94 (m, 1H), 6.77-6.70 (m, 1H), 5.50 (s, 1H), 5.35(s, 2H), 2.90-2.60 (m, 2H), 1.47-1.27 (m, 1H), 1.38 (s, 9H), 1.25-1.05(m, 1H), 0.97-0.80 (m, 1H), 0.65-0.55 (m, 2H), 0.32-0.10 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) −137.30; MS (ES+): 390.4 (M+1); Chiral puritychecked by performing chiral HPLC using chiral AD-H column, 1 mL/min,Solvent: 90% Hexane, 10% EtOH, 0.1% TEA, UV=260 nM, 25° C. (>99.99 ee);Optical Rotation [α]_(D)=(−) 78.49 [0.265, MeOH].

Step-5: Preparation of (2R,4S)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate(39f)

Compound 39f was prepared from(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxylicacid (29b) (225 mg, 0.732 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) and ethyl 2-ethoxyquinoline-1(2H)-carboxylate (181 mg, 0.732 mmol)using the reaction and workup conditions as reported in step 10 ofScheme 1 to afford (2R,4S)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate(39f) (235 mg, 0.346 mmol, 47.3% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.78 (d, J=93.3 Hz, 1H), 8.59-8.47 (m, 2H), 8.32 (s,1H), 8.29-8.06 (m, 1H), 7.51 (dt, J=6.6, 1.4 Hz, 2H), 7.43-7.07 (m, 6H),5.99 (2s, 1H, rotamers), 5.51 (m, 1H), 4.44 (m, 1H), 3.68 (m, 2H),2.78-2.51 (m, 2H), 2.35-2.15 (m, 1H), 1.33 (2s, 9H, rotamers), 1.15 (s,10H), 0.92 (m, 2H), 0.73-0.57 (m, 1H), 0.42-0.30 (m, 2H), 0.00-−0.13 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.66, −130.04 (rotamers); MS (ES+)679.5 (M+1), 701.5 (M+Na), (ES−) 677.5 (M−1), 713.5 (M+Cl); OpticalRotation [α]_(D)=(−) 55.55 [0.18, MeOH].

Step-6: Preparation of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(39g)

Reaction of (2R,4S)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate(39f) (200 mg, 0.295 mmol) in methanol (10 mL) with hydrochloric acid(1.964 mL, 5.89 mmol) gave after workup and purification as reported instep 6 of Scheme 4(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(39g) (169 mg, 0.289 mmol, 98% yield) as a hydrochloride salt which wasused as such for next step; MS (ES−) 509.4 (M+Cl).

Step-7:(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(39h)

Reaction of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(39g) (160 mg, 0.274 mmol) in tetrahydrofuran (25 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (61.3 mg, 0.247 mmol) using sodiumbicarbonate as base according to procedure reported in step 3 of Scheme13 gave after purification by flash column chromatography(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(98 mg, 0.156 mmol, 56.9% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.74 (s, 1H), 9.25 (s, 1H), 8.47-8.41 (m, 2H), 8.30 (d, J=2.4Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.81 (dd,J=8.9, 2.6 Hz, 1H), 7.54 (dt, J=6.5, 1.3 Hz, 2H), 7.41-7.33 (m, 4H),7.33-7.25 (m, 1H), 7.15 (dd, J=7.3, 1.7 Hz, 2H), 5.95 (s, 1H), 4.80-4.65(m, 1H), 4.00 (d, J=10.5 Hz, 1H), 3.90 (d, J=10.4 Hz, 1H), 2.68 (dd,J=13.1, 9.6 Hz, 1H), 2.31 (m, 3H), 2.21 (t, J=8.1 Hz, 2H), 1.12-0.96 (m,2H), 0.70-0.53 (m, 1H), 0.45-0.26 (m, 2H), −0.01-−0.14 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −129.43; MS (ES+) 629.4 (M+1), 651.4, 653.4 (M+Na),(ES−) 627.4, 629.4 (M−1); Optical Rotation [α]_(D)=(+) 7.209 [0.265,MeOH]; Analysis calculated for C₃₄H₃₄ClFN₆O₃.0.5H₂O; C, 63.99; H, 5.53;N, 13.17. Found: C, 64.02; H, 5.63; N, 12.86.

Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(40a)

Reaction of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-2-carboxamide(39g) (250 mg, 0.428 mmol) in dichloromethane (20 mL) with4-chlorophenyl isocyanate (1n) (0.049 mL, 0.385 mmol) and sodiumbicarbonate (719 mg, 8.56 mmol) according to procedure reported in step9 Scheme 1 gave after purification by flash column chromatography(silica gel, 12 g eluting with CMA 80 in chloroform)(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(40a) (134 mg, 0.213 mmol, 49.8% yield) as an off white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.69 (s, 1H), 8.53 (s, 1H), 8.49-8.37 (m, 2H), 8.16(d, J=7.8 Hz, 1H), 7.61-7.53 (m, 4H), 7.43-7.34 (m, 4H), 7.33-7.25 (m,3H), 7.17 (s, 1H), 7.14 (d, J=1.3 Hz, 1H), 5.97 (s, 1H), 4.68 (dd,J=9.7, 2.7 Hz, 1H), 3.93 (d, J=10.1 Hz, 1H), 3.83 (d, J=10.0 Hz, 1H),2.72 (dd, J=13.1, 9.8 Hz, 1H), 2.39-2.10 (m, 5H), 1.12-0.97 (m, 2H),0.73-0.56 (m, 1H), 0.43-0.28 (m, 2H), −0.00-−0.10 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −129.82; MS (ES−), 626.5, 628.5 (M−1); Analysiscalculated for C₃₅H₃₅ClFN₅O₃.0.5H₂O: C, 65.98; H, 5.70; N, 10.99. Found:C, 65.94; H, 5.86; N, 10.69; Optical Rotation [α]_(D)=(+) 65.14 [0.175,MeOH].

Preparation of(2R,4S)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylamino)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(41a)

To a solution of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(39h) (100 mg, 0.159 mmol) in methanol (10 mL) was added acetic acid (1drop) paraformaldehyde (23.86 mg, 0.795 mmol), sodium borohydride (30.1mg, 0.795 mmol) and stirred at room temperature for 8 h. Additionalparaformaldehyde (23.86 mg, 0.795 mmol) and sodium borohydride (30.1 mg,0.795 mmol) was added to the reaction and stirred at room temperatureovernight. The reaction was concentrated in vacuum and the residueobtained was purified by flash column chromatography (silica gel, 12 geluting with CMA 80 in chloroform) to afford((2R,4S)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylamino)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(41a) (74 mg, 0.115 mmol, 72.4% yield) free base as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 9.73 (s, 1H), 9.25 (s, 1H), 8.50-8.41 (m, 2H),8.34-8.27 (m, 1H), 8.10 (d, J=7.1 Hz, 1H), 7.91 (dd, J=9.1, 0.8 Hz, 1H),7.82 (dd, J=9.0, 2.7 Hz, 1H), 7.59-7.48 (m, 2H), 7.43-7.34 (m, 3H),7.35-7.26 (m, 2H), 7.16 (dd, J=10.5, 8.8 Hz, 1H), 7.11-7.00 (m, 1H),5.94 (s, 1H), 4.71 (d, J=7.5 Hz, 1H), 4.10-3.85 (m, 2H), 2.75-2.63 (m,1H), 2.25 (m, 3H), 1.94 (s, 4H, N-Me and NH), 1.05-0.74 (m, 2H),0.70-0.56 (m, 1H), 0.40-0.24 (m, 2H), −0.06-−0.18 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −129.21; MS (ES+) 643.3 (M+1), 665.3, 667.3 (M+Na),(ES−) 641.4, 643.3 (M−1). The free base of compound 41a (100 mg, 0.159mmol) was converted to HCl salt in methanol (10 mL) using conc. HCl(0.101 mL, 0.303 mmol) to afford on freeze drying (2R,4S)-N1-(5-choropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylamino)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxamide(41a) (64 mg, 0.089 mmol, 88% yield) as a white powder; ¹H NMR (300 MHz,DMSO-d₆) δ 10.31 (s, 2H), 9.96 (s, 1H), 9.29 (s, 1H), 8.80 (d, J=5.3 Hz,2H), 8.31 (d, J=2.5 Hz, 1H), 8.17 (d, J=6.7 Hz, 1H), 7.95-7.77 (m, 2H),7.66 (d, J=5.3 Hz, 2H), 7.53 (d, J=7.6 Hz, 2H), 7.49-7.17 (m, 5H),4.87-4.58 (m, 1H), 4.11-3.84 (m, 2H), 2.78-2.54 (m, 3H), 2.47-2.13 (m,6H), 1.19-0.98 (m, 1H), 0.96-0.77 (m, 1H), 0.76-0.61 (m, 1H), 0.45-0.30(m, 2H), −0.00-−0.10 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −124.81; MS(ES+) 665.4, 667.4 (M+Na), (ES−) 641.5, 643.5 (M−1), 677.3, 679.4(M+Cl); Optical Rotation [α]_(D)=(+) 6.0 [0.19, MeOH].

Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(42l) Step-1: Preparation of (E)-ethyl 3-cyclopropylacrylate (42b)

To a solution of 1-(triphenylphosphoranylidene)pentan-2-one (42a) (994g, 2853 mmol) in dichloromethane (3000 mL) was addedcyclopropanecarbaldehyde (200 g, 2853 mmol) and stirred at roomtemperature for 20 h. The reaction mixture was concentrated to 1/3volume diluted with hexane (1000 mL) and concentrated in vacuum to getrid of dichloromethane. The reaction mixture was diluted with hexane(3000 mL) stirred for 10 mins. The solid obtained of triphenylphospineoxide was removed by filtration with washings of hexane (2×400 mL). Thefiltrate was concentrated to afford (E)-ethyl 3-cyclopropylacrylate(42b) (410 g, 2925 mmol, 103% yield) as a colorless oil, which was usedas such for next step without purification; ¹H NMR (300 MHz, DMSO-d₆) δ6.38 (dd, J=15.4, 10.2 Hz, 1H), 5.93 (d, J=15.4 Hz, 1H), 4.08 (q, J=7.1Hz, 2H), 1.64 (dtt, J=10.2, 8.0, 4.6 Hz, 1H), 1.19 (td, J=7.1, 1.0 Hz,3H), 0.98-0.82 (m, 2H), 0.75-0.62 (m, 2H).

Step-2: Preparation of ethyl 3-cyclopropylpropanoate (42c)

To a solution of (E)-ethyl 3-cyclopropylacrylate (42b) (290 g, 2069mmol) in methanol (2000 mL) cooled to 5° C. was added cobalt (II)chloride hexahydrate (24.61 g, 103 mmol) followed by dropwise additionof a solution of sodium tetrahydroborate (157 g, 4138 mmol) in DMF (500mL) at such a rate that internal temperature was not allowed to raiseabove 10° C. The reaction mixture was stirred for 1 h at 5° C., pouredinto water (5000 mL) and stirred for 15 mins. The resultant blacksuspended solution was filtered over celite pad, pad, washed withdichloromethane (3×800 mL). The aqueous layer was separated andextracted with dichloromethane (2×600 mL). The dichloromethane layerswere combined washed with water (2×1500 mL), brine, dried over MgSO₄,filtered and concentrated under vacuum with bath temperature below 40°C. to afford ethyl 3-cyclopropylpropanoate (42c) (260 g, 88% yield) ascolorless liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 4.03 (q, J=7.1 Hz, 2H),2.33 (t, J=7.3 Hz, 2H), 1.41 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H),0.75-0.59 (m, 1H), 0.40-0.31 (m, 2H), 0.06-−0.06 (m, 2H).

Step-3: Preparation of 3-cyclopropyl-N-methoxy-N-methylpropanamide (42d)

To a solution of ethyl 3-cyclopropylpropanoate (42c) (260 g, 1828 mmol)in THF (2000 mL) cooled to −10° C. was added N,O-dimethylhydroxylaminehydrochloride (268 g, 2743 mmol), followed by drop-wise addition ofisopropylmagnesiumchloride (2743 mL, 5485 mmol, 2M in THF). The mixturewas stirred at −10° C. for 2 h, quenched with sat. NH₄Cl solution (4000mL) and allowed to warm to room temperature. The THF layer was separatedand aqueous layer was extracted with EtOAc (2×1000 mL). The organiclayers were combined washed with brine, dried over MgSO₄, filtered andconcentrated in vacuum to afford3-cyclopropyl-N-methoxy-N-methylpropanamide (42d) (240 g, 1527 mmol, 83%yield) as an orange liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.66 (s, 3H),3.07 (s, 3H), 2.44 (t, J=7.6 Hz, 2H), 1.39 (q, J=7.3 Hz, 2H), 0.76-0.62(m, 1H), 0.42-0.31 (m, 2H), 0.08-−0.09 (m, 2H).

Step-4: Preparation of1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (42e)

To a solution of 3-cyclopropyl-N-methoxy-N-methylpropanamide (42d) (240g, 1527 mmol) in THF (2000 mL) cooled to 5° C. was added drop-wise afreshly prepared solution of(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c)(1908 mL, 1527 mmol, 1M in THF) maintaining internal temperature around5° C. during addition. The reaction was stirred at 5° C. for 2 h,quenched with 3N HCl (1000 mL) and stirred for 2 h. The mixture wasbasified with solid NaHCO₃ and extracted with ethyl acetate (2×500 mL).The combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated in vacuum to afford crude 42e. The crudematerial was dissolved isopropanol (150 mL) and stirred over night. Thesolid obtained was collected by filtration, washed with isopropanol anddried to afford 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one(42e) (90 g, 28.46% first crop) as a white solid. The filtrate wasconcentrated, kept at room temperature for 6 h and the solid obtainedwas collected by filtration to afford1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (42e) (50 g,15.81%, second crop) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.38(dd, J=8.9, 2.2 Hz, 1H), 7.18 (ddd, J=8.4, 4.7, 2.2 Hz, 1H), 7.09 (dd,J=11.1, 8.4 Hz, 1H), 5.41 (s, 2H), 2.98 (t, J=7.3 Hz, 2H), 1.48 (q,J=7.2 Hz, 2H), 0.82-0.65 (m, 1H), 0.41-0.33 (m, 2H), 0.10-−0.02 (m, 2H);MS (ES+) 208.2 (M+1), (ES−) 206.2 (M−1); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.24;

Step-5: Preparation of1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (42f)

To a solution of 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one(42e) (13.63 g, 65.8 mmol) in THF (150 mL) and Methanol (300 mL) at 0°C. was added sodium borohydride (5.08 g, 132 mmol) and stirred at 0° C.for 1 h. The reaction mixture was allowed to warm to room temperatureovernight. The reaction mixture was diluted with ethyl acetate (800 mL),neutralized with acetic acid, washed with water (2×300 mL), brine (300mL), dried over MgSO4, filtered and concentrated in vacuum. The residuewas purified by flash column chromatography [silica gel, eluting withhexanes/ethyl acetate (1:0 to 4:1)] to afford1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (42f) (11.47 g, 53.8mmol, 83% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 6.86 (dd,J=11.5, 8.2 Hz, 1H), 6.72 (dd, J=9.1, 2.1 Hz, 1H), 6.42 (ddd, J=8.3,4.5, 2.1 Hz, 1H), 5.03 (s, 2H), 4.98 (d, J=4.1 Hz, 1H), 4.40-4.30 (m,1H), 1.71-1.48 (m, 2H), 1.26-1.01 (m, 2H), 0.73-0.54 (m, 1H), 0.45-0.24(m, 2H), 0.02-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −138.16; MS (ES+)210.1 (M+1); (ES−) 208.1 (M−1).

Step-6: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(42g)

Compound 42g was prepared from1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (42f) (700 mg, 3.35mmol), (2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylicacid (36a) (820 mg, 3.35 mmol) and ethyl2-ethoxyquinoline-1(2H)-carboxylate (827 mg, 3.35 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 toafford (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(42g) (1.273 g, 2.92 mmol, 87% yield) as a colorless syrup; ¹H NMR (300MHz, DMSO-d₆) δ 9.42 (2s, 1H, rotamers), 7.87 (dd, J=35.9, 7.7 Hz, 1H,rotamers), 7.17 (dd, J=10.8, 8.4 Hz, 1H), 7.06 (s, 1H), 5.19 (d, J=4.4Hz, 1H), 4.49 (q, J=5.9 Hz, 1H), 4.29 (m, 1H), 3.99 (m, 1H), 3.59 (dd,J=11.0, 5.5 Hz, 1H), 3.34-3.30 (m, 1H), 3.22 (2s, 3H, rotamers),2.45-2.25 (m, 1H), 2.19-1.89 (m, 1H), 1.77-1.51 (m, 2H), 1.36 (2s, 9H,rotamers), 1.26-1.05 (m, 2H), 0.74-0.53 (m, 1H), 0.46-0.22 (m, 2H),−0.011-−0.098 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.81, −130.11rotamers.

Step-7: Preparation of (2R,4R)-tert-butyl2-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(42h)

To a solution of triphenylphosphine (451 mg, 1.718 mmol) indichloromethane (15 mL) at 0° C. was added bromine (70.8 μL, 1.374 mmol)and stirred for 15 mins. To the reaction at 0° C. was added a premixedsolution containing (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(42g) (300 mg, 0.687 mmol) and imidazole (117 mg, 1.718 mmol) indichloromethane (15 mL). The reaction was allowed to warm to roomtemperature over a period of 1 h and concentrated in vacuum. The residueobtained was purified by flash column chromatography (silica gel,eluting with ethyl acetate in hexanes 20 to 30%) to afford(2R,4R)-tert-butyl2-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(42h) (279 mg, 0.559 mmol, 81% yield) as light brown semi solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.56 (2s, 1H, rotamers), 8.05 (2m, 1H, rotamers),7.37-7.04 (m, 2H), 5.30 (t, J=7.5 Hz, 1H), 4.32 (m, 1H), 4.07-3.90 (m,1H), 3.59 (dd, J=11.1, 5.4 Hz, 1H), 3.43-3.28 (m, 1H), 3.23 (2s, 3H,rotamers), 2.62-2.23 (m, 2H), 2.20-1.89 (m, 1H), 1.37 (2s, 9H,rotamers), 1.30-1.02 (m, 3H), 0.79-0.63 (m, 1H), 0.48-0.29 (m, 2H),0.03-−0.049 (m, 2H). 19F NMR (282 MHz, DMSO-d₆) δ −126.1 rotamers. MS(ES+) 499.46, 501.47 (M+1), 521.45, 523.46 (M+Na), (ES−) 497.41, 499.37(M−1).

Step-8: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(42j)

To a stirred solution of pyridin-2-ol (42i) (252 mg, 2.65 mmol) inacetonitrile (25 mL) was added potassium carbonate (381 mg, 2.76 mmol),heated at reflux for 1 h and cooled to room temperature. To the reactionmixture was added a solution of (2R,4R)-tert-butyl2-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(42h) (265 mg, 0.531 mmol) in acetonitrile (15 mL) and heated at refluxovernight. The reaction mixture was concentrated in vacuum and theresidue was suspended in water (25 mL), extracted with ethyl acetate(3×50 mL). The ethyl acetate layers were combined, washed with water(2×25 mL), brine (25 mL), dried and concentrated in vacuum.

The crude residue was purified by flash column chromatography (silicagel, 12 g eluting with 9:1 mixture of ethyl acetate and methanol inhexanes 0 to 60%) to afford (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(42j) (120 mg, 0.234 mmol, 44.0% yield) as an off white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.55 (2s, 1H, rotamers), 7.79 (s, 1H, rotamers),7.62 (s, 1H), 7.42-7.31 (m, 1H), 7.25 (dd, J=10.5, 8.6 Hz, 1H), 7.18(bs, 1H), 6.39 (dd, J=9.2, 1.4 Hz, 1H), 6.23 (tt, J=6.7, 1.6 Hz, 1H),6.06 (t, J=8.2 Hz, 1H), 4.27 (m, 1H), 3.97 (m, 1H), 3.58 (m, 1H),3.45-3.23 (m, 1H), 3.21 (2s, 3H, rotamers), 2.61-2.23 (m, 1H), 2.23-2.08(m, 2H), 2.00-1.83 (m, 1H), 1.34 (2s, 9H, rotamers), 1.17-0.96 (m, 2H),0.79-0.61 (m, 1H), 0.48-0.28 (m, 2H), 0.10-−0.10 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −126.20, −127.58 rotamers; MS (ES+) 514.6 (M+1), 536.6(M+Na), (ES−) 512.5 (M−1), 548.6 (M+Cl).

Step-9: Preparation of(2R,4R)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(42k)

Compound 42k was prepared from (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(42j) (110 mg, 0.214) using 3N HCl in methanol (0.714 mL, 2.142 mmol)according to the procedure reported in step 6 of Scheme 4 for to furnish(2R,4R)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(42k) (96 mg, 0.213 mmol, 100% yield) hydrochloride as a light brownsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.46 (s, 1H), 10.08 (s, 1H), 8.79(s, 1H), 7.89-7.56 (m, 2H), 7.50-7.11 (m, 2H), 6.40 (d, J=9.3 Hz, 1H),6.25 (d, J=7.2 Hz, 1H), 6.07 (s, 1H), 4.49 (d, J=5.6 Hz, 1H), 4.09 (s,1H), 3.39 (s, 1H), 3.35-3.21 (m, 1H), 3.19 (2s, 3H two diastereomers),2.64-2.51 (m, 1H), 2.31-2.15 (m, 4H), 1.25-0.93 (m, 2H), 0.79-0.61 (m,1H), 0.49-0.28 (m, 2H), 0.07-−0.10 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.71, −124.73 (diastereomers); MS (ES+) 414.5 (M+1), 436.5 (M+Na),(ES−) 4112.5 (M−1), 448.5 (M+Cl).

Step-10: Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(421)

Reaction of(2R,4R)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(42k) (96 mg, 0.213 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (80 mg, 0.320 mmol) using 1N aqueoussodium bicarbonate (4.27 mL, 4.27 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(42i) (113 mg, 0.199 mmol, 93% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.55 (s, 1H), 9.16 (s, 1H), 8.30 (dd, J=2.6, 0.7 Hz, 1H),7.90 (dd, J=9.1, 0.8 Hz, 1H), 7.87-7.77 (m, 2H), 7.65 (d, J=6.9 Hz, 1H),7.35 (ddd, J=8.8, 6.5, 2.0 Hz, 1H), 7.29-7.12 (m, 2H), 6.38 (dd, J=9.2,1.3 Hz, 1H), 6.22 (t, J=6.7 Hz, 1H), 6.05 (t, J=8.0 Hz, 1H), 4.59 (dd,J=9.2, 3.8 Hz, 1H), 4.08-3.97 (m, 1H), 3.82-3.60 (m, 2H), 3.22 (2s, 3H,diastereomers), 2.42-2.32 (m, 1H), 2.29-2.04 (m, 3H), 1.18-0.93 (m, 2H),0.78-0.62 (m, 1H), 0.44-0.29 (m, 2H), 0.04-−0.11 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −126.35; MS (ES+) 568.6, 570.6 (M+1), 590.5, 592.5(M+Na), (ES−) 566.5, 568.5 (M−1); IR (KBr) 3420, 3077, 2998, 2932, 1659,1520 cm⁻¹; Analysis calculated for C₂₉H₃₁ClFN₅O₄.0.5H₂O: C, 60.36; H,5.59; N, 12.14. Found: C, 60.76; H, 5.66; N, 11.82.

Preparation of((2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(43m) Step-1: Preparation of(S)(+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(43a)

Compound (43a) was prepared from1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (42e) (100.865 g,487 mmol), (S)-2-methylpropane-2-sulfinamide (86 g, 681 mmol) andtetraisopropoxytitanium (287 mL, 973 mmol) using procedure as reportedin step 3 of scheme 31 to afford(S)(+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(43a) (64 g, 206 mmol, 42.4% yield) as a light brown solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.33 (d, J=8.9 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 5.39 (s,2H), 3.33-3.05 (m, 2H), 1.54-1.37 (m, 2H), 1.21 (s, 9H), 0.85-0.63 (m,1H), 0.46-0.32 (m, 2H), 0.15-0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−129.79; MS (ES+) 311.4 (M+1), 333.4 (M+Na), (ES−) 309.4 (M−1), 345.3(M+Cl); Optical rotation [α]_(D)=(+) 20.0 [0.18, MeOH].

Step-2: Preparation of(S)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(43b)

To a solution of(S)(+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(43a) (64 g, 206 mmol) in tetrahydrofuran (1.5 L) cooled to −78° C. wasadded Lithium triethylborohydride (618 mL, 618 mmol) slowly over aperiod of 2 h maintaining the reaction temperature below −75° C. Thereaction was stirred at −78° C. for 3 h and allowed to warm to roomtemperature overnight. Reaction mixture was cooled to 0° C. quenched andwith saturated aqueous NH4Cl (600 mL). The layers were separated andaqueous layer was extracted with ethyl acetate (2×1000 mL). The combinedorganic layers were washed with water (2×1000 mL), brine (500 mL), driedover MgSO4 filtered and concentrated in vacuum to afford(S)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(43b) (127 g, 203 mmol, 99% yield) which was used without purificationin the next; MS (ES+) 313.4 (M+1), 335.4 (M+Na), (ES−) 311.4 (M−1),347.3 (M+Cl).

Step-3: Preparation of methyl5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate(43c)

To a biphasic solution of(S)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(43b) (127 g, 203 mmol) in ethyl acetate (635 mL) and saturated aqueousNaHCO₃ (635 mL) was added methyl chloroformate (23.61 mL, 305 mmol) andstirred vigorously at room temperature overnight. The layers wereseparated and aqueous layer was extracted with ethyl acetate (2×1 L).The combined organic layers were washed with brine, dried, filtered,concentrated in vacuum and purified by chromatography to afford methyl5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate(43c) (75.344 g, 203 mmol, 100% yield) as a gummy solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.29 (s, 1H), 7.56 (dd, J=7.9, 2.2 Hz, 1H), 7.15 (dd,J=10.6, 8.4 Hz, 1H), 7.05 (ddd, J=8.5, 4.8, 2.2 Hz, 1H), 5.31 (d, J=4.8Hz, 1H), 4.28-4.09 (m, 1H), 3.65 (s, 3H), 2.06-1.88 (m, 1H), 1.78-1.61(m, 1H), 1.25-1.11 (m, 1H), 1.06 (s, 9H), 1.06-0.88 (m, 1H), 0.74-0.55(m, 1H), 0.42-0.29 (m, 2H), −0.01-−0.09 (m, 2H); 19F NMR (282 MHz,DMSO-d₆) δ −126.77; MS (ES+) 371.5 (M+1), 393.5 (M+Na), (ES−) 369.4(M−1), 405.4 (M+Cl); Optical rotation [α]_(D)=(+) 74.4 [0.18, MeOH].

Step-4: Preparation of (−)-methyl5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (43d)

To a solution of methyl5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate(43c) (75 g, 202 mmol) in methanol (1000 mL) was added 3M HCl inMethanol (337 mL, 1012 mmol) stirred for 30 mins and concentrated invacuum to dryness. The residue was dissolved in water (500 mL) basifiedwith saturated sodium bicarbonate and extracted with ethyl acetate(3×1500 mL).

The combined organic layers were washed with water (2×300 mL), brine(500 mL), dried, filtered and concentrated in vacuum to afford(−)-methyl 5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (43d)(63.5 g, 238 mmol, 118% yield) as a thick syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 9.26 (s, 1H), 7.55 (dd, J=8.0, 2.0 Hz, 1H), 7.20-7.06 (m,1H), 3.77 (t, J=6.8 Hz, 1H), 3.65 (s, 3H), 3.50-3.14 (m, 2H), 2.50-2.28(m, 1H), 1.60 (m, 2H), 1.24-0.94 (m, 2H), 0.72-0.53 (m, 1H), 0.41-0.27(m, 2H), −0.02-−0.11 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.37; MS(ES+) 267.4 (M+1), (ES−) 265.3 (M−1); Optical rotation [α]_(D)=(−) 3.0[0.2, MeOH].

Step-5: Preparation of (+)-methyl5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(43f)

To a solution of (−)-methyl5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (43d) (63 g, 237mmol) in dichloromethane (1000 mL) was addeddihydro-2H-pyran-2,6(3H)-dione (43e) (29.7 g, 260 mmol) at roomtemperature and stirred for 30 mins. To the reaction was added acetylchloride (336 mL, 4731 mmol) heated at reflux 2 h and concentrated invacuum to dryness. The solid separated was (crude weight 100 g)crystallized from isopropanol (250 mL) to afford (+)-methyl5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(43f) (51.5 g, 142 mmol, 60.1% yield) as white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.29 (s, 1H), 7.65-7.41 (m, 1H), 7.19-6.86 (m, 2H), 5.71 (dd,J=9.2, 6.5 Hz, 1H), 3.65 (s, 3H), 2.61 (qd, J=7.6, 7.0, 3.2 Hz, 4H),2.42-2.11 (m, 2H), 1.81 (p, J=6.5 Hz, 2H), 1.22-0.99 (m, 2H), 0.76-0.56(m, 1H), 0.44-0.28 (m, 2H), 0.11-−0.12 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −126.82; MS (ES+) 363.5 (M+1), 385.5 (M+Na), (ES−) 361.5;Optical rotation [α]_(D)=(+) 101.9 [0.21, MeOH].

Step-6: Preparation of methyl5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(43g)

To a solution of (+)-methyl5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(43f) (51 g, 141 mmol) in dichloromethane (1407 mL) at −78° C. was addeddiisobutylaluminum hydride (422 mL, 422 mmol) and stirred at −78° C. for1 h. Reaction was quenched with methanol (30 mL), saturated aqueoussodium potassium tartarate (1 L) and allowed to 0° C. The slurry wasstirred for 2 h, layers were separated and aqueous layer was extractedwith dichloromethane (2×500 mL). The combined organic layers were washedwith water (2×500 mL), brine (200 mL) dried, filtered and concentratedin vacuum to afford methyl5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(43g) (51.3 g, 141 mmol, 100% yield,) which was used as such in nextstep without purification; MS (ES−) 363.5 (M−1).

Step-7: Preparation of (+)-methyl5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(43h)

To a stirred solution of methyl5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate(43g) (52 g, 143 mmol) in dichloromethane (1586 mL) was addedtriethylamine (119 mL, 856 mmol), cooled to 0° C. and addedmethanesulfonyl chloride (22.24 mL, 285 mmol). The reaction was stirredat room temperature overnight, diluted with dichloromethane (100 mL) andwater (500 mL). Layers were separated and aqueous layer was extractedwith dichloromethane (2×500 mL). The organic layers were combined washedwith water (2×250 mL), brine (250 mL), dried, filtered and concentratedin vacuum. The crude residue was purified by flash column chromatography(silica gel, eluting with ethyl acetate in hexanes 0 to 100%) to afford(+)-methyl5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(43h) (51.6 g, 149 mmol, 104% yield) as a colorless syrup; ¹H NMR (300MHz, DMSO-d₆) δ 9.35 (s, 1H), 7.66-7.50 (m, 1H), 7.18 (dd, J=10.7, 8.5Hz, 1H), 7.06 (m, 1H), 6.15 (dt, J=7.9, 1.6 Hz, 1H), 5.64 (dd, J=9.8,6.3 Hz, 1H), 5.17 (dt, J=8.2, 4.4 Hz, 1H), 3.66 (s, 4H, Me, NH),2.50-2.36 (m, 2H), 2.26-2.14 (m, 1H), 2.06-1.87 (m, 1H), 1.43 (m, 1H),1.28-0.99 (m, 2H), 0.72 (m, 1H), 0.44-0.30 (m, 2H), 0.11-−0.13 (m, 2H);19F NMR (282 MHz, DMSO-d₆) δ −126.08; MS (ES+) 369.5 (M+Na), (ES−) 345.4(M−1); Optical rotation [α]_(D)=(+) 123.9 [0.255, MeOH].

Step-8: Preparation of (+)-methyl5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(43i)

To a stirred solution of (+)-methyl5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(43h) (5.95 g, 17.18 mmol) in dichloromethane (200 mL) was addedmanganese dioxide (7.47 g, 86 mmol) and heated to reflux for 10 h.Additional manganese dioxide (7.47 g, 86 mmol) was added in 7installments over a period of 72 h. The reaction mixture was filteredwashed with dichloromethane and concentrated in vacuum. The cruderesidue obtained was purified by flash column chromatography (silicagel, eluting with ethyl acetate in hexanes 0 to 100%) to afford(+)-methyl5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(43i) (2.962 g, 8.60 mmol, 50.1% yield) as light black oil; ¹H NMR (300MHz, DMSO-d₆) δ 9.40 (s, 1H), 7.75-7.59 (m, 2H), 7.38 (ddd, J=8.8, 6.5,2.0 Hz, 1H), 7.28-7.14 (m, 2H), 6.45-6.37 (m, 1H), 6.25 (td, J=6.7, 1.5Hz, 1H), 6.08 (t, J=8.1 Hz, 1H), 3.67 (s, 3H), 2.22 (q, J=7.7 Hz, 2H),1.28-0.93 (m, 2H), 0.84-0.62 (m, 1H), 0.47-0.31 (m, 2H), 0.11-−0.13 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −125.29; MS (ES+) 345.4 (M+1), 367.4(M+Na), (ES−) 343.4 (M−1), 379.3 (M+Cl); Optical rotation [α]_(D)=(+)240.0 [0.05, MeOH].

Step-9: Preparation of(+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one(43j)

To a solution of (+)-methyl5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(43i) (2.9 g, 8.42 mmol) in methanol (75 mL) was added aqueous sodiumhydroxide (14.03 mL, 84 mmol, 6N), heated to reflux for 10 h andconcentrated in vacuum. The residue was diluted with water (200 mL)extracted with ethyl acetate (3×200 mL). The organic layers werecombined, washed with water (2×100 mL), brine (100 mL), dried, filteredand concentrated in vacuum. The crude residue was purified by flashcolumn chromatography (silica gel, eluting with ethyl acetate in hexanes0 to 60 to 100%) to afford of(+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one(43j) (2.173 g, 7.59 mmol, 90% yield) as a syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 7.58 (dd, J=6.9, 2.0 Hz, 1H), 7.35 (ddd, J=8.8, 6.5, 2.0 Hz,1H), 6.94 (dd, J=11.5, 8.3 Hz, 1H), 6.75 (dd, J=8.7, 2.3 Hz, 1H), 6.53(ddd, J=8.4, 4.3, 2.3 Hz, 1H), 6.39 (dd, J=9.1, 1.3 Hz, 1H), 6.21 (td,J=6.7, 1.5 Hz, 1H), 5.99 (dd, J=9.1, 7.0 Hz, 1H), 5.19 (s, 2H),2.23-2.03 (m, 2H), 1.11 (m, 1H), 0.99 (m, 1H), 0.79-0.62 (m, 1H),0.46-0.28 (m, 2H), 0.08-−0.12 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−136.31; MS (ES+) 287.4 (M+1), 309.4 (M+Na), 573.7 (2M+1), 595.7(2M+Na), (ES−) 285.3 (M−1), 321.3 (M+Cl); Optical rotation [α]_(D)=(+)296.25 [0.16, MeOH].

Step-10: Preparation of (2R,4R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(43k)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(36a) (158 mg, 0.513 mmol),(+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one(43j) (286 mg, 1.0 mmol) in tetrahydrofuran (20 mL) with ethyl2-ethoxyquinoline-1(2H)-carboxylate (247 mg, 1.0 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with ethyl acetate in hexanes 0 to 100%) afforded(2R,4R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(43k) (462 mg, 0.900 mmol, 90% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.51 (2s, 1H, rotamers), 7.87 (m, 1H), 7.71-7.56 (m, 1H),7.36 (ddd, J=8.8, 6.5, 2.0 Hz, 1H), 7.25 (dd, J=10.5, 8.5 Hz, 1H), 7.17(d, J=8.1 Hz, 1H), 6.39 (dd, J=9.1, 1.4 Hz, 1H), 6.23 (td, J=6.7, 1.4Hz, 1H), 6.07 (t, J=8.0 Hz, 1H), 4.42-4.21 (m, 1H), 4.00-3.92 (m, 1H),3.59 (dd, J=11.1, 5.5 Hz, 1H), 3.35-3.26 (m, 1H), 3.21 (2s, 3H,rotamers), 2.51-2.28 (m, 1H), 2.20 (m, 2H), 2.11-1.85 (m, 1H), 1.34 (2s,9H, rotamers), 1.26-0.93 (m, 2H), 0.72 (m, 1H), 0.37 (m, 2H), 0.10-−0.10(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −125.99, −127.39; MS (ES+) 514.6(M+1), 536.6 (M+Na), (ES−) 512.6 (M−1), 548.5 (M+Cl); Optical rotation[α]_(D)=(+) 248 [0.115, MeOH].

Step-11: Preparation of(2R,4R)-N-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(431)

Compound 431 was prepared from (2R,4R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(43k) (450 mg, 0.876 mmol) using 3N HCl in methanol (2.92 mL, 8.76 mmol)according to the procedure reported in step 6 of Scheme 4 for to furnish(2R,4R)-N-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(431) (394 mg, 0.876 mmol, 100% yield) hydrochloride salt as a as lightbrown syrup; 1H NMR (300 MHz, DMSO-d₆) δ 10.45 (s, 1H), 10.17-9.94 (m,1H), 8.95-8.64 (m, 2H), 7.73 (ddd, J=32.9, 7.3, 2.1 Hz, 2H), 7.37 (ddd,J=8.8, 6.5, 2.0 Hz, 1H), 7.33-7.25 (m, 2H), 6.40 (dd, J=9.1, 1.3 Hz,1H), 6.24 (td, J=6.8, 1.5 Hz, 1H), 6.07 (t, J=8.1 Hz, 1H), 4.63-4.35 (m,1H), 4.09 (d, J=3.8 Hz, 1H), 3.50-3.21 (m, 1H), 3.19 (s, 3H), 2.63-2.52(m, 1H), 2.22 (m, 3H), 1.11 (m, 2H), 0.71 (m, 1H), 0.38 (m, 2H),0.06-−0.11 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −124.56; MS (ES+) 414.5(M+1), 436.5 (M+Na), 827.8 (2M+1), (ES−) 412.5 (M−1), 448.4 (M+Cl);Optical rotation [α]_(D)=(+) 170.9 [0.055, MeOH].

Step-12: Preparation of((2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(43m)

Reaction of(2R,4R)-N-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(431) (394 mg, 0.876 mmol) in tetrahydrofuran (50 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (327 mg, 1.314 mmol) using 1Naqueous sodium bicarbonate (17.52 mL, 17.52 mmol) as base according toprocedure reported in step 3 of Scheme 13 gave after purification byflash column chromatography((2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(43m) (245 mg, 0.431 mmol, 49.2% yield) as white solid; 1H NMR (300 MHz,DMSO-d₆) δ 9.55 (s, 1H), 9.17 (s, 1H), 8.30 (dd, J=2.7, 0.7 Hz, 1H),7.90 (dd, J=9.0, 0.8 Hz, 1H), 7.88-7.78 (m, 2H), 7.65 (dd, J=7.0, 2.0Hz, 1H), 7.35 (ddd, J=8.9, 6.5, 2.0 Hz, 1H), 7.24 (dd, J=10.5, 8.6 Hz,1H), 7.19-7.12 (m, 1H), 6.38 (dd, J=9.2, 1.4 Hz, 1H), 6.22 (td, J=6.7,1.5 Hz, 1H), 6.05 (t, J=8.0 Hz, 1H), 4.59 (dd, J=9.2, 4.0 Hz, 1H),4.12-3.96 (m, 1H), 3.83-3.62 (m, 2H), 3.22 (s, 3H), 2.44-2.30 (m, 1H),2.29-2.04 (m, 3H), 1.24-0.91 (m, 2H), 0.79-0.61 (m, 1H), 0.45-0.29 (m,2H), 0.04-−0.09 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −126.21; MS (ES+)568.5, 570.6 (M+1), 590.5, 592 (M+Na), (ES−) 566.5, 568.5 (M−1); Opticalrotation [α]_(D)=(+) 229.54 [0.325, MeOH]; Analysis calculated forC₂₉H₃₁ClFN₅O₄: C, 61.32; H, 5.50; Cl, 6.24; N, 12.33. Found: C, 61.06;H, 5.53; Cl, 6.02; N, 12.27.

Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(44e) Step-1: Preparation of(+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-3,4-dihydropyridin-2(1H)-one(44a)

Compound (44a) was prepared from (+)-methyl5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate(43h) (4 g, 11.55 mmol) and aqueous NaOH (19.25 mL, 115 mmol 6N) usingprocedure as reported in step 9 of scheme 43 to afford(+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-3,4-dihydropyridin-2(1H)-one(44a) (3.22 g, 11.17 mmol, 97% yield) as a syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 6.91 (dd, J=11.5, 8.3 Hz, 1H), 6.69 (dd, J=8.8, 2.3 Hz, 1H),6.44 (ddd, J=8.5, 4.4, 2.3 Hz, 1H), 6.09 (dt, J=7.7, 1.6 Hz, 1H), 5.56(dd, J=10.1, 5.9 Hz, 1H), 5.21-5.04 (m, 3H), 2.48-2.36 (m, 2H),2.27-2.12 (m, 2H), 1.98-1.80 (m, 2H), 1.21-0.94 (m, 2H), 0.81-0.61 (m,1H), 0.45-0.28 (m, 2H), 0.07-0.01 (m, 1H), −0.01-−0.08 (m, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −136.82; MS (ES+) 289.4 (M+1), 311.4 (M+Na), (ES−)287.4 (M−1); Optical rotation [α]_(D)=(+) 144.4 [0.205, MeOH].

Step-2: Preparation of(+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)piperidin-2-one(44b)

Compound 44b was prepared by reduction of(+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-3,4-dihydropyridin-2(1H)-one(44a) (3.2 g, 11.10 mmol) for 1 h according to the reaction and workprocedure reported in step 2 of Scheme 13 using palladium hydroxide(0.779 g, 1.11 mmol) in ethyl acetate (50 mL) to afford(+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)piperidin-2-one(44b) (2.846 g, 9.80 mmol, 88% yield) as a light yellow oil; 1H NMR (300MHz, DMSO-d₆) δ 6.91 (dd, J=11.5, 8.3 Hz, 1H), 6.70 (dd, J=8.9, 2.2 Hz,1H), 6.42 (ddd, J=8.4, 4.3, 2.2 Hz, 1H), 5.68 (dd, J=9.3, 6.7 Hz, 1H),5.11 (s, 2H), 3.12-2.93 (m, 1H), 2.82-2.63 (m, 1H), 2.28 (m, 2H),1.95-1.75 (m, 2H), 1.75-1.42 (m, 4H), 1.25-0.95 (m, 2H), 0.82-0.67 (m,1H), 0.42-0.35 (m, 2H), 0.11-−0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−137.07; MS (ES+) 291.4, 313.4 (M+Na), ES−) 289.4 (M−1), 325.4 (M+Cl);Optical rotation [α]_(D)=(+) 164.0 [0.15, MeOH].

Step-3: Preparation of methyl (2R,4R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(44c)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(36a) (245 mg, 1 mmol),(+)-1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)piperidin-2-one(44b) (290 mg, 1.0 mmol) in tetrahydrofuran (20 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (247 mg, 1.0 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with ethyl acetate in hexanes 0 to 100%) methyl(2R,4R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(44c) (453 mg, 0.875 mmol, 88% yield) as a colorless syrup; ¹H NMR (300MHz, DMSO-d₆) δ 9.50 (2s, 1H, rotamers), 8.04-7.66 (m, 1H), 7.22 (dd,J=10.8, 8.5 Hz, 1H), 7.10-6.99 (m, 1H), 5.78 (t, J=8.0 Hz, 1H),4.48-4.20 (m, 1H), 4.06-3.91 (m, 1H), 3.59 (dd, J=11.1, 5.6 Hz, 1H),3.41 (s, 1H), 3.22 (2s, 3H, rotamers), 3.14-3.01 (m, 1H), 2.82-2.67 (m,1H), 2.50-2.04 (m, 2H), 2.01-1.79 (m, 4H), 1.77-1.56 (m, 3H), 1.60-1.46(m, 1H), 1.36 (2s, 9H, rotamers), 1.29-0.98 (m, 2H), 0.85-0.64 (m, 1H),0.47-0.30 (m, 2H), 0.14-−0.08 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−127.42, −128.68 rotamers; MS (ES+) 518.6 (M+1), 540.6 (M+Na), (ES−)516.5 (M−1), 552.5 (M+Cl); Optical rotation [α]_(D)=(+)126.6 [0.15,MeOH].

Step-4: Preparation of(2R,4R)-N-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(44d)

Compound 44d was prepared from methyl (2R,4R)-tert-butyl2-(5-((+)-3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(44c) (400 mg, 0.773 mmol) using 3N HCl in methanol (2.58 mL, 7.73 mmol)according to the procedure reported in step 6 of Scheme 4 to furnish(2R,4R)-N-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(44d) (351 mg, 0.773 mmol, 100% yield) as a light brown syrup; ¹H NMR(300 MHz, DMSO-d₆) δ 10.51 (s, 1H), 10.37 (s, 1H), 8.78 (s, 1H), 7.73(dd, J=7.6, 2.2 Hz, 1H), 7.27 (dd, J=10.6, 8.5 Hz, 1H), 7.14 (ddd,J=8.1, 4.8, 2.2 Hz, 1H), 5.79 (dd, J=9.5, 6.5 Hz, 1H), 4.71-4.35 (m,1H), 4.22-4.02 (m, 1H), 3.47-3.35 (m, 1H), 3.36-3.20 (m, 1H), 3.20 (s,3H), 3.14-3.04 (m, 1H), 2.82-2.67 (m, 1H), 2.65-2.52 (m, 1H), 2.39-2.18(m, 3H), 2.06-1.85 (m, 2H), 1.79-1.44 (m, 4H), 1.31-0.98 (m, 2H),0.84-0.64 (m, 1H), 0.48-0.31 (m, 2H), 0.12-−0.07 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −125.55; MS (ES+) 418.6 (M+1), 440.5 (M+Na), (ES−) 416.5(M−1), 452.5 (M+Cl).

Step-5: Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(44e)

Reaction of(2R,4R)-N-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(44d) (340 mg, 0.749 mmol) in tetrahydrofuran (50 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (280 mg, 1.125 mmol) using 1Naqueous sodium bicarbonate (15 mL, 15.00 mmol) as base according toprocedure reported in step 3 of Scheme 13 gave after purification byflash column chromatography (silica gel, 12 g eluting with CMA 80 inchloroform 0-100%) pure(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(44e) (210 mg, 0.367 mmol, 48.9% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.53 (s, 1H), 9.18 (s, 1H), 8.30 (dd, J=2.6, 0.8 Hz,1H), 7.91 (dd, J=9.0, 0.8 Hz, 1H), 7.87-7.73 (m, 2H), 7.21 (dd, J=10.7,8.5 Hz, 1H), 7.10-6.99 (m, 1H), 5.85-5.68 (m, 1H), 4.60 (dd, J=9.1, 3.9Hz, 1H), 4.12-3.98 (m, 2H), 3.83-3.65 (m, 2H), 3.24 (s, 3H), 3.14-3.00(m, 1H), 2.83-2.64 (m, 1H), 2.47-2.32 (m, 1H), 2.35-2.20 (m, 1H),2.18-2.03 (m, 1H), 2.01-1.81 (m, 2H), 1.75-1.56 (m, 3H), 1.61-1.44 (m,1H), 1.27-0.97 (m, 2H), 0.83-0.64 (m, 1H), 0.47-0.30 (m, 2H), 0.10-−0.07(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.47; MS (ES+) 572.6 (M+1),594.5, 596.5 (M+Na), (ES−) 570.5, 572.5 (M−1); Optical rotation[α]_(D)=(+) 174.3 [0.21, MeOH].

Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide(45c) Step-1: Preparation of (2R,4S)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-phenylpyrrolidine-1-carboxylate(45a)

Reaction of(2R,4S)-1-(tert-butoxycarbonyl)-4-methoxy-4-phenylpyrrolidine-2-carboxylicacid (34a) (160 mg, 0.498 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (194 mg, 0.498 mmol) in tetrahydrofuran (10 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (123 mg, 0.498 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 25 g,eluting with CMA 80 in chloroform 0 to 100%) (2R,4S)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-phenylpyrrolidine-1-carboxylate(45a) (287 mg, 0.414 mmol, 83% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.49 (2s, 1H, rotamers), 8.77-8.28 (m, 2H), 8.04 (m, 1H),7.53-7.08 (m, 8H), 5.48 (m, 1H), 4.35 (m, 1H), 3.77 (s, 1H), 3.41 (s,2H), 2.85 (2s, 3H, rotamers), 2.78-2.35 (m, 3H), 1.33 (2s, 9H,rotamers), 1.15 (m, 10H), 1.02-0.82 (m, 2H), 0.64 (m, 1H), 0.36 (m, 2H),0.04-−0.15 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −128.09, −129.50rotamers; MS (ES+) 693.7 (M+1), 715.7 (M+Na), (ES−) 691.7 (M−1), 727.7(M+Cl); Optical rotation [α]_(D)=(−) 8.0 [0.075, MeOH].

Step-2: Preparation of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide(45b)

Reaction of (2R,4S)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-phenylpyrrolidine-1-carboxylate(45a) (280 mg, 0.404 mmol) in methanolic HCl (2.694 mL, 8.08 mmol)followed by workup and purification as reported in step 6 of Scheme 4gave(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide(45b) (227 mg, 0.404 mmol, 100% yield) hydrochloride salt which was usedas such for next step; MS (ES+) 489.5 (M+1), (ES−) 487.4 (M−1), 523.5(M+Cl).

Step-3: Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide(45c)

Reaction of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxy-4-phenylpyrrolidine-2-carboxamide(45b) (111 mg, 0.444 mmol) in tetrahydrofuran (50 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (227 mg, 0.404 mmol) using 1Naqueous sodium bicarbonate (8.08 mL, 8.08 mmol) as base according toprocedure reported in step 3 of Scheme 13 gave after purification byflash column chromatography (silica gel, 12 g eluting with CMA 80 inchloroform 0-100%)(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxy-4-phenylpyrrolidine-1,2-dicarboxamide(45c) (50 mg, 0.078 mmol, 19.24% yield) as white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.46 (s, 1H), 9.23 (s, 1H), 8.59-8.36 (m, 2H), 8.31 (d, J=2.6Hz, 1H), 7.97-7.88 (m, 2H), 7.81 (dd, J=9.0, 2.6 Hz, 1H), 7.43 (d, J=4.2Hz, 4H), 7.40-7.32 (m, 3H), 7.21-7.09 (m, 2H), 4.65 (t, J=6.2 Hz, 1H),4.23 (d, J=10.8 Hz, 1H), 3.90 (d, J=10.8 Hz, 1H), 2.84 (s, 3H), 2.62 (d,J=6.4 Hz, 2H), 2.40-2.25 (m, 2H), 2.26-2.12 (m, 2H), 1.12-0.94 (m, 2H),0.73-0.54 (m, 1H), 0.43-0.27 (m, 2H), 0.01-−0.17 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −128.48; MS (ES+) 643.6, 645.7 (M+1), (ES−) 641.6, 643.6(M−1); Optical rotation [α]_(D)=(+) 99.23 [0.26, MeOH].

Preparation of((2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(46k) Step-1: Preparation of 2-methyl-isonicotinic acid (46b)

To a solution of 2, 4-dimethyl-pyridine (46a) (100 g, 933.245 mmol) inwater (1000 mL) was added potassium permanganate (294.97 g, 1866.489mmol) portion-wise over a period of 2 h. The resulting reaction mixturewas heated at 80° C. for 12 h. The reaction mixture was cooled to roomtemperature, filtered through celite bed and filtrate was concentratedunder reduced pressure to a volume of 250 mL at 50° C. The obtainedsolution was cooled to 0° C. and pH was adjusted to 3 using 1N HCl(temperature between 0° C. to 5° C.). The solid obtained was collectedby filtration washed with chilled water and dried to afford2-methylisonicotinic acid (46b) (22.3 g, yield: 17.42%); ¹H NMR (D₂O) δ8.52 (s, 1H), 7.94-7.90 (m, 2H), 2.69 (s, 3H); MS (+) 138.1 (M+1).

Step-2: Preparation of N-methoxy-N,2-dimethylisonicotinamide (46c)

To a stirred solution of 2-methylisonicotinic acid (46b) (17.8 g,129.798 mmol) in N,N-dimethylformamide (180 mL) was addedN,N-diisopropylethylamine (67.105 gm, 519.192 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI,40.299 g, 259.596 mmol) and hydroxybenzotriazole (HOBt, 39.753 g,259.596 mmol) at room temperature. The resulting reaction mixture wasstirred for 0.5 h at room temperature followed by the addition of N, Odimethyl hydroxyl amine hydrochloride (13.8 g, 141,479 mmol). Thereaction mixture was stirred at room temperature for 12 h, quenched withwater (500 mL), extracted with ethyl acetate (5×500 mL). The combinedorganic layers were dried over sodium sulfate, filtered andconcentrated. The residue obtained was purified by column chromatographyto afford N-methoxy-N,2-dimethylisonicotinamide (46c) (23 g, 98.4%yield) as a reddish thick solid; ¹H NMR (CDCl₃) δ 8.29-8.27 (s, 1H),7.08-7.01 (m, 2H), 3.27 (s, 3H), 3.07 (s, 3H), 2.32 (s, 3H); MS (ES+)181.1 (M+1).

Step-3: Preparation of 1-(2-methylpyridin-4-yl)ethanone (46d)

To a stirred solution of N-methoxy-N,2-dimethylisonicotinamide (46c) (26g, 144.281 mmol) in THF (520 mL) was added MeLi (6.342 g, 288.562 mmol,1M solution in THF) under nitrogen atmosphere at −78° C. The reactionmixture was warmed to room temperature over a period of 1 h, quenchedwith saturated NH₄Cl solution at 0° C. The resulting reaction mixturewas extracted with ethyl acetate and the organic layer was washed withwater and brine, dried over sodium sulfate, filtered and concentrated.The residue obtained was purified by column chromatography to afford1-(2-methylpyridin-4-yl)ethanone (46d) (11 g, 56.4% yield) as a reddishthick liquid; ¹H NMR (CDCl₃) δ 8.61-8.59 (d, 1H), 7.51-7.45 (d, 1H),7.45-7.44 (m, 1H), 4.05-4.02 (s, 3H); MS (ES+) 136.1 (M+1).

Step-4: Preparation of3-cyclopropyl-1-(2-methylpyridin-4-yl)prop-2-en-1-one (46e)

Compound 46e was prepared from 1-(2-methylpyridin-4-yl)ethanone (46d)(11.g, 81.383 mmol) according to the procedure reported in step 1 ofscheme 31 gave after purification by column chromatography3-cyclopropyl-1-(2-methylpyridin-4-yl)prop-2-en-1-one (46e) (4.5 g,29.5% yield) as a reddish liquid; MS (ES+) 188.1 (M+1).

Step-5: Preparation of3-cyclopropyl-1-(2-methylpyridin-4-yl)propan-1-one (46f)

Compound 46f was prepared from 3-cyclopropyl-1-pyridin-4-yl-propenone(46e) (8 g, 42.726 mmol) according to the procedure reported in step 2of scheme 31 gave after purification by column chromatography3-cyclopropyl-1-(2-methylpyridin-4-yl)propan-1-one (46f) (5.5 g 68.1%yield) as yellow liquid; ¹H NMR (CDCl₃) δ 8.61-8.59 (d, 1H), 7.53-7.48(m, 1H), 7.46-7.20 (m, 1H), 3.02-2.97 (m, 2H), 2.58 (s, 3H), 1.60-1.53(m, 2H), 0.85-0.71 (m, 1H), 0.71-0.67 (m, 2H), 0.42-0.37 (m, 2H); MS(ES+) 190.2 (M+1).

Step-6: Preparation of(R)-N-(3-cyclopropyl-1-(2-methylpyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(46g)

Compound 46g was prepared from3-cyclopropyl-1-(2-methylpyridin-4-yl)propan-1-one (46f) (5.5 g, 29.062mmol) and R-2-methyl propane-2-sulfinamide (4.209 g, 34.729 mmol)according to the procedure reported in step 3 of scheme 31 gave afterpurification by column chromatography(R)-N-(3-cyclopropyl-1-(2-methylpyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(46g) (7 g, 82.44% yield) as a yellow liquid; ¹H NMR (CDCl₃) δ 8.59-8.49(m, 1H), 7.51-7.33 (m, 2H), 3.32-2.98 (m, 2H), 2.54 (s, 3H), 1.54-1.49(m, 2H), 1.42-1.13 (m, 9H), 0.85-0.71 (m, 1H), 0.71-0.67 (m, 2H),0.42-0.37 (m, 2H); MS (ES+) 293.2 (M+1).

Step-7: Preparation of(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(46h)

Compound 46h was prepared from(R)-N-(3-cyclopropyl-1-(2-methylpyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(46g) (5.5 g, 29.062 mmol) and R-2-methyl propane-2-sulfinamide (2 g,6.839 mmol) and freshly prepared(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c)(19.10 mL, 15.28 mmol) according to the procedure reported in step 4 ofscheme 31 gave after purification by column chromatography(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(46h) (0.8 g, 29.0% yield) as a reddish thick liquid; ¹H NMR (DMSO-d₆) δ8.36-8.34 (d, 1H), 7.24 (s, 1H), 7.12-7.10 (d, 1H), 6.95-6.88 (m, 1H),6.76-6.73 (m, 1H), 5.38-5.32 (s, 1H), 5.17-5.11 (s, 2H), 2.58-2.45 (s,3H), 2.05-2.01 (m, 2H), 1.55-1.51 (m, 2H), 1.28-1.10 (m, 9H), 0.67-0.45(m, 1H), 0.39-0.37 (m, 2H), 0.03-0.00 (m, 2H); MS (ES+) 404.3 (M+1);Optical rotation [α]_(D)=(−) 55.0 [0.28,MeOH]

Step-8: Preparation of (2R,4R)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(46i)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(36a) (245 mg, 1.0 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(46h) (404 mg, 1.0 mmol) in tetrahydrofuran (50 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (247 mg, 1.0 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (2R,4R)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(46i) (485 mg, 0.769 mmol, 77% yield) as a colorless solid; ¹H NMR (300MHz, DMSO-d6) δ 9.47 (2s, 1H, rotamers), 8.33 (d, J=5.4 Hz, 1H),8.09-7.77 (m, 1H), 7.26-7.15 (m, 3H), 7.08 (dd, J=5.3, 1.7 Hz, 1H), 5.41(2s, 1H, rotamers), 4.46-4.16 (m, 1H), 3.97 (dd, J=9.1, 4.1 Hz, 1H),3.57 (dd, J=11.0, 5.4 Hz, 1H), 3.36-3.24 (m, 1H), 3.21 (m, 3H),2.65-2.53 (m, 1H), 2.45-2.39 (m, 4H), 2.01-1.84 (m, 1H), 1.33 (2s, 9H,rotamers), 1.14 (m, 10H), 0.90 (m, 2H), 0.71-0.54 (m, 1H), 0.42-0.32 (m,2H), −0.00-−0.17 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d6) δ −127.87 (q,J=8.1, 7.2 Hz), −128.88 rotamers; MS (ES+) 631.7 (M+1), 653.7 (M+Na),(ES−) 629.6 (M−1); Optical rotation [α]_(D)=(−) 50.2 [0.175, MeOH].

Step-9: Preparation of(2R,4R)-N-(5-(-1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(46j)

Reaction of (2R,4R)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(46i) (475 mg, 0.753 mmol) in 3N methanolic HCl (5.020 mL, 15.06 mmol)followed by workup and purification as reported in step 6 of Scheme 4gave(2R,4R)-N-(5-(-1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(46j) (376 mg, 0.753 mmol, 100% yield) hydrochloride salt as on offwhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.69 (s, 1H), 10.40 (s, 1H),9.76 (s, 3H), 9.55 (bs, 1H), 8.90-8.67 (m, 2H), 7.89-7.76 (m, 2H),7.76-7.62 (m, 1H), 7.53-7.28 (m, 2H), 4.61-4.43 (m, 1H), 4.22-3.98 (m,1H), 3.49-3.33 (m, 1H), 3.33-3.22 (m, 1H), 3.17 (s, 3H), 2.69 (d, J=6.8Hz, 3H), 2.66-2.50 (m, 1H), 2.50-2.39 (m, 1H), 2.31-2.12 (m, 1H),1.34-1.15 (m, 1H), 1.16-0.94 (m, 1H), 0.79-0.60 (m, 1H), 0.46-0.33 (m,2H), 0.10-0.00 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −122.19; MS (ES+)427.5 (M+1), (ES−) 425.5 (M−1), 461.4 (M+Cl).

Step-10: Preparation of((2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(46k)

Reaction of gave(2R,4R)-N-(5-(-1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(46j) (370 mg, 0.741 mmol) in tetrahydrofuran (55 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (203 mg, 0.815 mmol) using sodiumbicarbonate (14.82 mL, 14.82 mmol, 1N aqueous) as base according toprocedure reported in step 3 of Scheme 13 gave after purification byflash column chromatography((2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(46k) (190 mg, 0.327 mmol, 44.1% yield) as white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.45 (s, 1H), 9.15 (s, 1H), 8.33-8.24 (m, 2H), 7.95-7.82 (m,2H), 7.81 (dd, J=9.0, 2.6 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.16-7.09 (m,3H), 4.57 (dd, J=9.2, 3.9 Hz, 1H), 4.11-3.97 (m, 1H), 3.85-3.63 (m, 2H),3.20 (s, 3H), 2.48-2.38 (m, 1H), 2.40 (s, 3H), 2.35-2.21 (m, 2H),2.24-2.03 (m, 3H), 1.11-0.93 (m, 2H), 0.73-0.51 (m, 1H), 0.41-0.25 (m,2H), −0.02-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.45; MS (ES+)581.6, 583.6 (M+1), 603.6 (M+Na), 579.5 (M−1), 615.5, 617.5 (M+Cl);Optical rotation [α]_(D)=(+) 92.12 [0.33,MeOH]; Analysis calculated forC₃₀H₃₄ClFN₆O₃.0.75H₂O: C, 60.60; H, 6.02; N, 14.13. Found: C, 60.90; H,6.00; N, 14.17.

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-phenylpyrrolidine-1,2-dicarboxamide(47d) Step-1: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-phenylpyrrolidine-1-carboxylate(47b)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid(47a) (230 mg, 0.789 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (308 mg, 0.789 mmol) in tetrahydrofuran (10 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (195 mg, 0.789 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-phenylpyrrolidine-1-carboxylate(47b) (255 mg, 0.385 mmol, 48.7% yield) as a clear oil. MS (ES+) 663.7(M+1).

Step-2: Preparation of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-phenylpyrrolidine-2-carboxamide(47c)

Reaction of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-phenylpyrrolidine-1-carboxylate(47b) (255 mg, 0.385 mmol) in methanol (10 mL) using 4N HCl in dioxane(1.282 mL, 3.85 mmol) followed by workup and purification as reported instep 6 of Scheme 4 gave(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-phenylpyrrolidine-2-carboxamide(47c) (95 mg, 0.207 mmol, 53.9% yield) as a clear oil. ¹H NMR (300 MHz,CDCl₃) δ 10.26 (s, 1H), 8.65-8.57 (m, 1H), 8.54 (d, J=6.0 Hz, 2H),7.41-7.30 (m, 4H), 7.30-7.21 (m, 3H), 7.12-6.95 (m, 2H), 4.15 (dd,J=9.8, 2.8 Hz, 1H), 3.56-3.44 (m, 1H), 3.42-3.25 (m, 1H), 3.17 (t, J=9.3Hz, 1H), 2.67-2.52 (m, 4H), 2.42-2.30 (m, 3H), 1.29-1.03 (m, 2H),0.80-0.59 (m, 1H), 0.53-0.34 (m, 2H), −0.00 (m, 2H); ¹⁹F NMR (282 MHz,CDCl₃) δ −132.94; MS (ES+) 459.4 (M+1).

Step-3: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-phenylpyrrolidine-1,2-dicarboxamide(47d)

Reaction of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-phenylpyrrolidine-2-carboxamide(47c) (95 mg, 0.207 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (46.4 mg, 0.186 mmol) usingpotassium carbonate (71.6 mg, 0.518 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel, 12 g eluting with CMA 80 in chloroform0-50%)(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-phenylpyrrolidine-1,2-dicarboxamide(47d) (68 mg, 0.111 mmol, 53.5% yield) free base as a white solid, whichwas converted into hydrochloride salt (72 mg, 0.105 mmol, 50.7% yield)with HCl (3N in MeOH, 3 mL). ¹H NMR (300 MHz, DMSO-d6) δ 10.23-10.13 (m,1H), 9.79 (s, 3H), 9.26 (s, 1H), 9.01-8.88 (m, 2H), 8.30 (dd, J=2.6, 0.8Hz, 1H), 8.10 (dd, J=7.2, 2.5 Hz, 1H), 7.97-7.77 (m, 4H), 7.46-7.19 (m,7H), 4.95-4.76 (m, 1H), 4.28-4.02 (m, 1H), 3.63-3.58 (m, 1H), 2.62-2.53(m, 2H), 2.32 (td, J=15.7, 12.5, 6.1 Hz, 3H), 1.31-1.00 (m, 2H), 0.69(m, 1H), 0.48-0.31 (m, 2H), 0.09-0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−123.88; MS (ES+) 613.5 (M+1); Optical rotation [α]_(D)=(+) 101.4 [0.28,MeOH].

Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methylpyrrolidine-1,2-dicarboxamide(48d) Step-1: Preparation of (2R,4S)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methylpyrrolidine-1-carboxylate(48b)

Reaction of(2R,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(48a) (145 mg, 0.632 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (246 mg, 0.632 mmol) in tetrahydrofuran (10 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (156 mg, 0.632 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel, elutingwith 0-60% EtOAc in Hexane) (2R,4S)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methylpyrrolidine-1-carboxylate(48b) (248 mg, 0.413 mmol, 65.3% yield) as a clear oil. MS (ES+) 601.7(M+1).

Step-2: Preparation of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methylpyrrolidine-2-carboxamide(48c)

Reaction of (2R,4S)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methylpyrrolidine-1-carboxylate(48b) (246 mg, 0.409 mmol) in methanol (10 mL) using 4N HCl in dioxane(1.365 mL, 4.09 mmol) followed by workup and purification as reported instep 6 of Scheme 4 gave(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methylpyrrolidine-2-carboxamide(48c) (100 mg, 0.252 mmol, 61.6% yield) as a clear oil. 1H NMR (300 MHz,CDCl₃) δ 10.22 (s, 1H), 8.61-8.44 (m, 3H), 7.43-7.25 (m, 3H), 7.13-6.91(m, 2H), 4.13-4.01 (m, 1H), 3.31-3.13 (m, 1H), 2.79-2.67 (m, 1H),2.44-2.32 (m, 3H), 2.32-2.17 (m, 2H), 1.96-1.76 (m, 1H), 1.27-0.95 (m,6H), 0.80-0.71 (m, 1H), 0.71-0.60 (m, 1H), 0.54-0.31 (m, 2H), 0.00 (s,2H); 19F NMR (282 MHz, CDCl₃) δ −132.78; MS (ES+) 551.5 (M+1).

Step-3: Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methylpyrrolidine-1,2-dicarboxamide(48d)

Reaction of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methylpyrrolidine-2-carboxamide(48c) (95 mg, 0.207 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (46.4 mg, 0.186 mmol) usingpotassium carbonate (71.6 mg, 0.518 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel, 12 g eluting with CMA 80 in chloroform0-50%)(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methylpyrrolidine-1,2-dicarboxamide(48d) (68 mg, 0.111 mmol, 53.5% yield) free base as a white solid, whichwas converted into hydrochloride salt (72 mg, 0.105 mmol, 50.7% yield)with HCl (3N in MeOH, 3 mL). ¹H NMR (300 MHz, DMSO-d₆) δ 10.23-10.13 (m,1H), 9.79 (s, 3H), 9.26 (s, 1H), 9.01-8.88 (m, 2H), 8.30 (dd, J=2.6, 0.8Hz, 1H), 8.10 (dd, J=7.2, 2.5 Hz, 1H), 7.97-7.77 (m, 4H), 7.46-7.19 (m,7H), 4.95-4.76 (m, 1H), 4.28-4.02 (m, 1H), 3.63-3.58 (m, 1H), 2.62-2.53(m, 2H), 2.32 (td, J=15.7, 12.5, 6.1 Hz, 3H), 1.31-1.00 (m, 2H), 0.69(m, 1H), 0.48-0.31 (m, 2H), 0.09-0.01 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −123.88; MS (ES+) 613.5 (M+1); Optical rotation [α]_(D)=(+)144.4 [0.29, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methylpyrrolidine-1,2-dicarboxamide(49d) Step-1: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methylpyrrolidine-1-carboxylate(49b)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(49a) (90 mg, 0.393 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (153 mg, 0.393 mmol) in tetrahydrofuran (10 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (97 mg, 0.393 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methylpyrrolidine-1-carboxylate(49b) crude (160 mg, 67.8%), which was used as such in next step withoutfurther purification. MS (ES+) 601.7 (M+1).

Step-2: Preparation of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methylpyrrolidine-2-carboxamide(49c)

Reaction of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methylpyrrolidine-1-carboxylate(49b) (160 mg, 0.266 mmol) in methanol (10 mL) using 4N HCl in dioxane(0.888 mL, 2.66 mmol) followed by workup and purification as reported instep 6 of Scheme 4 gave(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methylpyrrolidine-2-carboxamide(49c) crude (66 mg, 62.5% yield), which was used as such in next stepwithout further purification. MS (ES+) 419.4 (M+Na).

Step-3: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methylpyrrolidine-1,2-dicarboxamide(49d)

Reaction of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methylpyrrolidine-2-carboxamide(49c) (66 mg, 0.166 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (37.3 mg, 0.150 mmol) usingpotassium carbonate (57.5 mg, 0.416 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel, 12 g eluting with CMA 80 in chloroform0-50%)(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methylpyrrolidine-1,2-dicarboxamide(49d) free base as a white solid, which was converted into hydrochloridesalt (12 mg, 0.019 mmol, 11.55% yield) with HCl (3N in MeOH, 3 mL); ¹HNMR (300 MHz, DMSO-d₆) δ 9.99 (s, 1H), 9.38 (s, 3H), 9.14 (s, 1H), 8.75(d, J=5.9 Hz, 2H), 8.28 (dd, J=2.6, 0.9 Hz, 1H), 8.03 (dd, J=7.3, 2.5Hz, 1H), 7.87-7.68 (m, 2H), 7.51 (d, J=5.5 Hz, 2H), 7.38 (dd, J=10.5,8.8 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 4.60 (t, J=8.1 Hz, 1H), 3.90-3.74(m, 1H), 3.10 (t, J=9.9 Hz, 1H), 2.67-2.20 (m, 4H), 1.44 (m, 1H),1.30-1.08 (m, 2H), 1.03 (d, J=6.3 Hz, 3H), 0.68 (m, 1H), 0.37 (m, 2H),0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −124.26; MS (ES+) 551.5 (M+1);Optical rotation [α]_(D)=(+) 130.9 [0.055, MeOH].

Preparation of (2R,4R)-benzyl2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethoxypyrrolidine-1-carboxylate(50d) Step-1: Preparation of(2R,4R)-1-(benzyloxycarbonyl)-4-ethoxypyrrolidine-2-carboxylic acid(50b)

To a solution of(2R,4R)-1-(benzyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(15a) (1.14 g, 4.30 mmol) in THF (20 mL) was added a solution of ethyl4-methylbenzenesulfonate (50a) (1.721 g, 8.60 mmol) in THF (2 mL),followed by NaOH (0.688 g, 17.19 mmol) and water (5 mL). The resultingmixture was heated to 55° C. overnight and concentrated in vacuum todryness. The residue was dissolved in water (10 mL), washed withdichloromethane (3×25 mL) and acidified to pH 2 with HCl (1.5N). Thereaction mixture was extracted with dichloromethane (3×25 mL) andorganic layers were combined, dried over MgSO4, filtered andconcentrated in vacuum. The residue was purified by flash chromatography(silica gel, eluting with 0-20% MeOH in chloroform) to obtain(2R,4R)-1-(benzyloxycarbonyl)-4-ethoxypyrrolidine-2-carboxylic acid(50b) (301 mg, 1.026 mmol, 23.88% yield) as a clear oil. MS (ES+) 316.3(M+Na).

Step-2: Preparation of (2R,4R)-benzyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethoxypyrrolidine-1-carboxylate(50c)

Reaction of(2R,4R)-1-(benzyloxycarbonyl)-4-ethoxypyrrolidine-2-carboxylic acid(50b) (300 mg, 1.023 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (398 mg, 1.023 mmol) in tetrahydrofuran (10 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (253 mg, 1.023 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(2R,4R)-benzyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethoxypyrrolidine-1-carboxylate(50c) (240 mg, 0.361 mmol, 35.3% yield) as a clear oil. ¹H NMR (300 MHz,DMSO-d₆) δ 9.51 (d, J=24.2 Hz, 1H), 8.49 (d, J=4.4 Hz, 2H), 7.87 (s,1H), 7.45-7.27 (m, 5H), 7.27-7.07 (m, 5H), 5.52 (d, J=12.7 Hz, 1H), 5.06(dd, J=21.2, 3.4 Hz, 2H), 4.45 (d, J=4.0 Hz, 1H), 4.07 (s, 1H), 3.67 (d,J=6.0 Hz, 1H), 3.38 (d, J=6.5 Hz, 2H), 2.05 (s, 1H), 1.13 (s, 11H),1.04-0.94 (m, 3H), 0.83 (m, 2H), 0.62 (s, 1H), 0.34 (s, 2H), −0.08 (s,2H); MS (ES+) 665.5 (M+1).

Step-3: (2R,4R)-benzyl2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethoxypyrrolidine-1-carboxylate(50d)

Reaction of (2R,4R)-benzyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethoxypyrrolidine-1-carboxylate(50c) (50 mg, 0.075 mmol) in methanol (5 mL) using 3N HCl in methanol(0.15 mL, 0.451 mmol) followed by workup and purification as reported instep 6 of Scheme 4 gave (2R,4R)-benzyl2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethoxypyrrolidine-1-carboxylate(50d) (24 mg, 0.043 mmol, 56.9% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.73 (d, J=17.2 Hz, 1H), 9.64-9.53 (m, 6H), 8.82 (d,J=5.4 Hz, 2H), 7.99-7.82 (m, 1H), 7.65 (m, 3H), 7.42-7.32 (m, 3H),7.29-7.12 (m, 3H), 5.15-4.97 (m, 2H), 4.47 (m, 1H), 4.09 (s, 1H), 3.71(s, 1H), 3.39 (q, J=7.0 Hz, 3H), 2.01 (m, 1H), 1.27-1.04 (m, 2H), 1.00(t, J=7.0 Hz, 3H), 0.69 (m, 1H), 0.39 (m, 2H), 0.08-−0.00 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −124.55; MS (ES+) 561.5 (M+1); 559.5 (M−1);Analysis calculated for C₃₂H₃₇FN₄O₄.2HCl.2H₂O: C, 57.40; H, 6.47; N,8.37. Found: C, 57.37; H, 6.25; N, 8.32; Optical rotation [α]_(D)=(+)43.6 [0.165, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethoxypyrrolidine-1,2-dicarboxamide(51b) Step-1: Preparation of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-ethoxypyrrolidine-2-carboxamide(51a)

Debenzylation by hydrogenation of (2R,4R)-benzyl2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-ethoxypyrrolidine-1-carboxylate(50d) (190 mg, 0.286 mmol) in methanol (5 mL), using palladium on carbon10% (15.21 mg, 0.086 mmol) as catalyst according to procedure reportedin step 2 of Scheme 13 gave(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-ethoxypyrrolidine-2-carboxamide(51a) (105 mg, 0.198 mmol, 69.2% yield), which was used as such in nextstep without further purification. MS (ES+) 531.4 (M+1).

Step-2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethoxypyrrolidine-1,2-dicarboxamide(51b)

Reaction of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-ethoxypyrrolidine-2-carboxamide(51a) (105 mg, 0.198 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (49.2 mg, 0.198 mmol) usingpotassium carbonate (68.4 mg, 0.495 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel, 12 g eluting with CMA 80 in chloroform0-50%)(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethoxypyrrolidine-1,2-dicarboxamide(51b) free base as a white solid, which was converted into hydrochloridesalt (60 mg, 0.092 mmol, 46.4% yield) with HCl (3N in MeOH, 3 mL); ¹HNMR (300 MHz, DMSO-d₆) δ 9.74 (s, 4H), 9.71-9.68 (m, 1H), 9.28 (s, 1H),8.97-8.86 (m, 2H), 8.30 (dd, J=2.5, 0.9 Hz, 1H), 7.96 (dd, J=7.3, 2.5Hz, 1H), 7.90-7.80 (m, 4H), 7.39 (dd, J=10.4, 8.7 Hz, 1H), 7.26 (ddd,J=8.7, 4.4, 2.4 Hz, 1H), 4.61 (dd, J=8.9, 4.4 Hz, 1H), 4.13 (p, J=4.9Hz, 1H), 3.79 (dd, J=10.7, 5.3 Hz, 1H), 3.64 (dd, J=10.7, 3.8 Hz, 1H),3.46-3.35 (m, 2H), 2.65-2.48 (m, 2H), 2.40 (ddd, J=14.0, 9.0, 5.1 Hz,1H), 2.07-1.98 (m, 1H), 1.34-1.15 (m, 1H), 1.14-1.02 (m, 1H), 1.01 (t,J=7.0 Hz, 3H), 0.76-0.59 (m, 1H), 0.45-0.31 (m, 2H), 0.07-0.00 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −124.72; Optical rotation [α]_(D)=(+) 7.209[0.54, MeOH]; Analysis calculated for C₃₀H₃₄ClFN₆O₃.3HCl.1.5H₂O: C,50.22; H, 5.62; Cl, 19.77; N, 11.71. Found: C, 50.55; H, 5.63; Cl,19.51; N, 11.49.

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-propoxypyrrolidine-1,2-dicarboxamide(52d) Step-1: Preparation of(2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidine-2-carboxylic acid(52a)

Alkylation of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(14b) (30.5 g, 132 mmol) with diisopropyl sulfate (33.4 mL, 203 mmol)using NaH (60% dispersion in oil) (32.5 g, 813 mmol) as base accordingto the procedure reported in scheme 15 step 1 gave(2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidine-2-carboxylic acid(52a) (23 g, 84 mmol, 63.7% yield) as a clear oil, which was used assuch in the next step without further purification. ¹H NMR (300 MHz,DMSO-d₆) δ 12.41 (s, 1H), 4.23-4.04 (m, 1H), 4.05-3.93 (m, 1H),3.62-3.44 (m, 1H), 3.37-3.22 (m, 2H), 3.23-3.11 (m, 1H), 2.43-2.21 (m,1H), 2.04-1.91 (m, 1H), 1.56-1.23 (m, 11H), 0.82 (t, J=7.4 Hz, 3H); MS(ES−) 272.3 (M−1).

Step-2: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-propoxypyrrolidine-1-carboxylate(52b)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidine-2-carboxylic acid(52a) (20 g, 73.0 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (26.5 g, 68.1 mmol) in tetrahydrofuran (300 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (18.09 g, 73.2 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-propoxypyrrolidine-1-carboxylate(52b) (43 g, 66.7 mmol, 98% yield), which was used as such in the nextstep without further purification. MS (ES+) 667.7 (M+Na).

Step-3: Preparation of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methylpyrrolidine-2-carboxamide(52c)

Reaction of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-propoxypyrrolidine-1-carboxylate(52b) (43 g, 66.7 mmol) in methanol (600 mL) using 4N HCl in dioxane(133 mL, 533 mmol) followed by workup and purification as reported instep 6 of Scheme 4 gave(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methylpyrrolidine-2-carboxamide(52c) (24.5 g, 55.6 mmol, 83% yield) as a yellow oil, which was used assuch in next step without further purification. MS (ES⁺) 441.6 (M+1).

Step-4: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-propoxypyrrolidine-1,2-dicarboxamide(52d)

Reaction of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methylpyrrolidine-2-carboxamide(52c) (24.5 g, 55.6 mmol) in tetrahydrofuran (550 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) 12.45 g, 50.1 mmol) using sodiumbicarbonate (28.0 g, 334 mmol) as base according to procedure reportedin step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel, eluting with ethyl acetate/MeOH (9:1) inhexane 0-50%) followed by reverse-phase column (eluting with methanol inwater 0-100%)(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-propoxypyrrolidine-1,2-dicarboxamide(52d) as a free base, which was converted into HCl salt with 3N HCl inMeOH (30 mL) to afford compound 52d (13.2 g, 39.5% yield) hydrochloridesalt as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.89 (s, 2H), 9.73(s, 1H), 9.37 (s, 1H), 8.97 (d, J=6.6 Hz, 2H), 8.31 (dd, J=2.5, 0.8 Hz,1H), 8.05-7.91 (m, 3H), 7.90-7.80 (m, 2H), 7.46-7.22 (m, 2H), 4.68-4.57(m, 1H), 4.18-4.06 (m, 1H), 3.81 (dd, J=10.6, 5.4 Hz, 1H), 3.64 (dd,J=10.5, 3.5 Hz, 1H), 3.32 (t, J=6.6 Hz, 2H), 2.65-2.52 (m, 2H),2.49-2.33 (m, 1H), 2.12-1.99 (m, 1H), 1.41 (q, J=6.8 Hz, 2H), 1.30-1.02(m, 2H), 0.77 (t, J=7.4 Hz, 3H), 0.76-0.60 (m, 1H), 0.43-0.30 (m, 2H),0.09-−0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −124.57; MS (ES+) 595.6(M+1); Optical rotation [α]_(D)=(+) 87.31 [0.52, MeOH]; Analysiscalculated for C₃₁H₃₆ClFN₆O₃.2HCl.3H₂O: C, 51.56; H, 6.14; Cl, 14.73; N,11.64. Found: C, 51.25; H, 5.82; Cl, 14.94; N, 11.53.

Preparation of(R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4,4-difluoropyrrolidine-1,2-dicarboxamide(53d) Step-1: Preparation of (R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4,4-difluoropyrrolidine-1-carboxylate(53b)

Reaction of(R)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid(53a) (225 mg, 0.896 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (349 mg, 0.896 mmol) in tetrahydrofuran (10 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (221 mg, 0.896 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4,4-difluoropyrrolidine-1-carboxylate(53b) which was used as such for next step; MS (ES+) 623.6 (M+1).

Step-2: Preparation of(R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4,4-difluoropyrrolidine-2-carboxamide(53c)

Reaction of (R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4,4-difluoropyrrolidine-1-carboxylate(53b) (243 mg, 0.39 mmol) in methanol (10 mL) using 4N HCl in dioxane(1.301 mL, 3.9 mmol) followed by workup and purification as reported instep 6 of Scheme 4 gave(R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4,4-difluoropyrrolidine-2-carboxamide(53c) which was used as such in next step without further purification.MS (ES+) 441.4 (M+Na).

Step-3: Preparation of(R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4,4-difluoropyrrolidine-1,2-dicarboxamide(53d)

Reaction of(R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4,4-difluoropyrrolidine-2-carboxamide(53c) (90 mg, 0.215 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (48.1 mg, 0.194 mmol) usingpotassium carbonate (74.3 mg, 0.538 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel, 12 g eluting with CMA 80 in chloroform0-50%)(R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4,4-difluoropyrrolidine-1,2-dicarboxamide(53d) free base as a white solid, which was converted into hydrochloridesalt using HCl (3N in MeOH, 3 mL) to obtain compound 53d (16 mg, 0.025mmol, 11.52% yield) hydrochloride salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.24-10.15 (m, 1H), 9.61 (s, 3H), 9.51 (s, 1H), 8.84(d, J=5.8 Hz, 2H), 8.32 (dd, J=2.1, 1.3 Hz, 1H), 8.01 (dd, J=7.3, 2.5Hz, 1H), 7.84 (dd, J=1.7, 1.1 Hz, 2H), 7.70 (d, J=5.5 Hz, 2H), 7.40 (dd,J=10.4, 8.8 Hz, 1H), 7.22 (q, J=5.4, 4.6 Hz, 1H), 4.92 (dd, J=9.0, 5.1Hz, 1H), 4.11 (dq, J=26.3, 12.5 Hz, 2H), 3.05-2.78 (m, 1H), 2.59-2.54(m, 2H), 2.46-2.41 (m, 1H), 1.14 (m, 2H), 0.81-0.55 (m, 1H), 0.47-0.31(m, 2H), 0.02 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −97.03, −123.95; MS(ES+) 573.4 (M+1); Optical rotation [α]_(D)=(+) 72.3 [0.155, MeOH];Analysis calculated for C₂₈H₂₈ClF₃N₆O₂.4HCl.2H₂O: C, 44.55; H, 4.81; N,11.13. Found: C, 44.49; H, 4.92; N, 11.07.

Preparation of(2R,4R)-N2-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxamide(54g) Step-1: Preparation of (R)-1-tert-butyl 2-methyl4-oxopyrrolidine-1,2-dicarboxylate (54b)

Oxidation of (2R,4R)-1-tert-butyl 2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate (54a) (9.5 g, 38.7 mmol) inanhydrous DCM (50 mL) using trichloroisocyanuric acid (9.45 g, 40.7mmol) and TEMPO (0.303 g, 1.937 mmol) according to the procedurereported in step 1 of Scheme 29 gave (R)-1-tert-butyl 2-methyl4-oxopyrrolidine-1,2-dicarboxylate (54b) (9.197 g, 98% yield) as ayellow oil. ¹H NMR (300 MHz, DMSO-d₆) δ 4.70-4.56 (m, 1H), 3.91-3.75 (m,1H), 3.68 (m, 4H), 3.19-3.01 (m, 1H), 2.67-2.50 (m, 1H), 1.39 (2s, 9H,rotamers).

Step-2: Preparation of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid (54c)

To a solution of (R)-1-tert-butyl 2-methyl4-oxopyrrolidine-1,2-dicarboxylate (54b) (3.5 g, 14.39 mmol) in THF (100mL) cooled to 0° C. was added trimethyl(trifluoromethyl)silane (2.189 g,15.40 mmol), TBAF (0.113 g, 0.432 mmol) and stirred at room temperatureovernight. The reaction was quenched with saturated aqueous NH₄Cl (75mL), stirred for 20 min added tetrabutylammonium fluoride (6.02 g, 23.02mmol) and stirred at room temperature for 3 h. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (3×100mL). The combined organic phases were washed with water, brine, driedover anhydrous MgSO4, filtered and concentrated in vacuum to dryness.The residue obtained was purified by flash chromatography (silica gel,eluting with 0-40% ethyl acetate in hexanes) to afford(2R,4R)-1-tert-butyl 2-methyl4-hydroxy-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxylate (54c) (2.818g, 9.0 mmol, 62.5% yield) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ6.59 (s, 1H), 4.70-4.38 (m, 1H), 3.76-3.61 (m, 3H, rotamers), 3.63-3.47(m, 2H), 2.66-2.53 (m, 1H), 2.11 (dd, J=13.2, 5.4 Hz, 1H), 1.47-1.27 (m,9H, rotamers); MS (ES+) 336.3 (M+Na).

Step-3: Preparation of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid (54d)

To a solution of (2R,4R)-1-tert-butyl 2-methyl4-hydroxy-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxylate (54c) (850mg, 2.71 mmol) in THF/H₂O (1:1, 20 mL) was added lithium hydroxide (325mg, 13.57 mmol) and heated at reflux for 1 h. The reaction mixture wasfiltered and concentrated in vacuum to afford(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid (54d) (842 mg, 2.81 mmol, 104% yield), which was used as such innext step without further purification. MS (ES−), 298.3 (M−1).

Step-4: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-1-carboxylate(54e)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid (54d) (842 mg, 2.82 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (850 mg, 2.71 mmol) in tetrahydrofuran (20 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (695 mg, 2.82 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-1-carboxylate(54e) (420 mg, 23.08% yield); MS (E+), 693.4 (M+23).

Step-5: Preparation of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide (54f)

Reaction of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-1-carboxylate(54e) (420 mg, 0.626 mmol) in ethanol (20 mL) using 4N HCl in dioxane(1.565 mL, 6.26 mmol) followed by workup and purification as reported instep 6 of Scheme 4 gave(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide(54f) (113 mg, 38.7% yield). MS (E+), 467.4 (M+1).

Step-6: Preparation of(2R,4R)-N2-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxamide(54g)

Reaction of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide(54f) (113 mg, 242 mmol) in tetrahydrofuran (10 mL) with phenyl5-chloropyridin-2-ylcarbamate (13b) (60.2 mg, 242 mmol) using potassiumcarbonate (100 mg, 727 mmol) as base according to procedure reported instep 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel, 12 g eluting with CMA 80 in chloroform0-50%) followed by reverse phase column chromatography (C-18 column,eluting with 0-100% MeOH in water)(2R,4R)-N2-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxamide(54g) as a free base, which was converted into HCl salt using HCl (3N inMeOH, 2 mL) to afford compound 54g hydrochloride salt (42 mg, 28% yield)as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.00 (s, 1H), 9.69 (s,3H), 9.46 (s, 1H), 9.00-8.79 (m, 2H), 8.31 (dd, J=2.4, 1.0 Hz, 1H), 8.06(dd, J=7.2, 2.5 Hz, 1H), 7.92-7.74 (m, 4H), 7.39 (dd, J=10.1, 8.5 Hz,1H), 7.29-7.04 (m, 2H), 4.84 (dd, J=9.1, 4.6 Hz, 1H), 4.05 (d, J=11.6Hz, 1H), 3.77 (d, J=11.7 Hz, 1H), 2.65 (m, 1H), 2.51 (m, 2H), 2.26-2.14(m, 1H), 1.23 (m, 1H), 1.08 (m, 1H), 0.67 (m, 1H), 0.36 (m, 2H), 0.02(m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −75.03, −80.20, −124.32. MS (ES+):521.3 (M+1); 519.3 (M−1).

Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-ethoxypyrrolidine-1,2-dicarboxamide(55a)

To a solution of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethoxypyrrolidine-1,2-dicarboxamide(51b) (240 mg, 0.413 mmol) at 0° C. in dichloromethane (10 mL) was addedpyridine (163 mg, 2.065 mmol), methanesulfonic anhydride (144 mg, 0.826mmol) and stirred at room temperature overnight. Additional pyridine (98mg, 1.239 mmol) and methanesulfonic anhydride (71.9 mg, 0.413 mmol) wereadded and the mixture was stirred for 2 h at room temperature. Thereaction mixture was quenched with water (10 mL) and extracted with DCM(3×20 mL). The organic layers were combined, dried, filtered andconcentrated in vacuum. The residue was purified by flash columnchromatography (silica gel, 12 g, eluting with 0-40% CMA80 in CHCl₃) togive(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-ethoxypyrrolidine-1,2-dicarboxamide(55a) (158 mg, 0.240 mmol, 58.0% yield) free base as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 9.52 (s, 1H), 9.16 (s, 1H), 8.51 (d, J=6.1 Hz,2H), 8.29 (d, J=2.6 Hz, 1H), 7.92-7.78 (m, 4H), 7.30-7.18 (m, 3H),7.14-7.03 (m, 1H), 4.59 (dd, J=9.0, 3.8 Hz, 1H), 4.12 (s, 1H), 3.76 (dd,J=10.8, 5.1 Hz, 1H), 3.65 (d, J=8.1 Hz, 1H), 3.40 (q, J=7.0 Hz, 2H),2.40-2.35 (m, 1H), 2.27 (s, 3H), 2.19-2.06 (m, 1H), 1.34-1.20 (m, 2H),0.99 (t, J=7.0 Hz, 3H), 0.91-0.78 (m, 2H), 0.63-0.44 (m, 1H), 0.37-0.21(m, 2H), −0.09-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −126.31; MS(ES+): 659.3 (M+1).

The free base (132 mg, 0.20 mmol) was converted to hydrochloride salt inMeOH (10 mL) using HCl (3N in MeOH) (0.03 mL, 1.001 mmol) to afford (136mg, 0.196 mmol, 98% yield) hydrochloride salt of compound 55a as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.87 (d, J=6.6Hz, 2H), 8.30 (d, J=2.0 Hz, 1H), 8.22 (s, 1H), 7.96 (d, J=6.5 Hz, 3H),7.93-7.79 (m, 2H), 7.34-7.21 (m, 1H), 7.16-7.05 (m, 1H), 4.61 (dd,J=8.9, 3.9 Hz, 1H), 4.19-4.06 (m, 2H), 3.84-3.72 (m, 2H), 3.66 (dd,J=10.7, 3.2 Hz, 2H), 3.41 (q, J=7.0 Hz, 2H), 2.77-2.62 (m, 1H),2.46-2.29 (m, 5H), 2.16-1.99 (m, 1H), 1.00 (t, J=7.0 Hz, 4H), 0.88-0.69(m, 1H), 0.64-0.50 (m, 1H), 0.32 (d, J=7.9 Hz, 2H), −0.01-−0.15 (m, 2H);¹⁹F NMR (282 MHz, DMSO) δ −125.42; MS (ES+): 659.3 (M+1); Opticalrotation [α]_(D)=(+) 76.47 [0.17, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-acetamido-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethoxypyrrolidine-1,2-dicarboxamide(56a)

Reaction of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethoxypyrrolidine-1,2-dicarboxamide(51b) (200 mg, 0.344 mmol) at 0° C. in dichloromethane using pyridineand acetic anhydride as reported in Scheme 55 gave(2R,4R)-N2-(5-((+)-1-acetamido-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-ethoxypyrrolidine-1,2-dicarboxamide(56a) (156 mg, 72.7% yield) free base as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 9.45 (s, 1H), 9.16 (s, 1H), 8.47-8.40 (m, 2H), 8.32-8.24 (m,2H), 7.94-7.82 (m, 2H), 7.80 (dd, J=9.0, 2.6 Hz, 1H), 7.29-7.22 (m, 2H),7.20-7.06 (m, 2H), 4.58 (dd, J=9.0, 3.9 Hz, 1H), 4.17-4.06 (m, 1H),3.82-3.70 (m, 1H), 3.70-3.60 (m, 1H), 3.49-3.30 (m, 2H), 2.60-2.50 (m,1H), 2.42-2.26 (m, 1H), 2.17-2.03 (m, 1H), 1.90 (s, 3H), 1.30-1.20 (m,2H), 1.03 (t, J=7.0 Hz, 3H), 0.91-0.78 (m, 1H), 0.70-0.52 (m, 1H),0.38-0.27 (m, 2H), −0.04-−0.18 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−127.98; Optical rotation [α]_(D)=(+) 70.59 [0.255, MeOH]. The free basewas converted to hydrochloride salt in methanol (10 mL) using HCl (3N inMeOH) (2.5 mL, 82 mmol) to afford hydrochloride salt of compound 56a(148 mg, 0.224 mmol, 98% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.58 (s, 1H), 9.28 (s, 1H), 8.83-8.69 (m, 3H), 8.30 (d, J=1.9Hz, 1H), 7.95 (m, 3H), 7.92-7.79 (m, 2H), 7.33-7.17 (m, 2H), 4.60 (dd,J=9.0, 4.3 Hz, 1H), 4.18-4.08 (m, 2H), 3.84-3.72 (m, 1H), 3.66 (dd,J=10.7, 3.2 Hz, 1H), 3.42 (q, J=7.0 Hz, 2H), 2.53 (m, 2H), 2.45-2.31 (m,1H), 2.11-2.01 (m, 1H), 1.94 (s, 3H), 1.03 (t, J=7.0 Hz, 5H), 0.71-0.57(m, 1H), 0.40-0.30 (m, 2H), −0.03-−0.14 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −126.67; MS (ES+): 623.3 (M+1); (ES−) 621.3 (M−1); Opticalrotation [α]_(D)=(+) 70.59 [0.255, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxamide(57d) Step-1: Preparation of(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid (57a)

Alkylation of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid (54d) (2.26 g, 7.55 mmol) in THF (50 mL) with dimethyl sulfate(1.905 g, 15.10 mmol) using sodium hydride (60% dispersion in mineraloil, 1.812 g, 45.3 mmol) as base according to the procedure reported inscheme 15 step 1 gave(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid (57a) (1.6 g, 5.11 mmol, 67.6% yield) as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 12.84 (s, 1H), 4.35 (t, J=9.3 Hz, 1H), 3.73-3.53 (m,2H), 3.36 (s, 3H), 2.71-2.51 (m, 1H), 2.38-2.24 (m, 1H), 1.39 (2s, 9H,rotamers).

Step-2: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-1-carboxylate(57b)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid (57a) (400 mg, 1.277 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (497 mg, 1.277 mmol) in tetrahydrofuran (20 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (316 mg, 1.277 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-1-carboxylate(57b) (640 mg, 0.935 mmol, 73.2% yield) as an off white solid.

Step-3: Preparation of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide(57c)

Reaction of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-1-carboxylate(57b) (640 mg, 0.935 mmol) in ethanol (200 mL) using 3N HCl in methanol(16 mL) followed by workup and purification as reported in step 6 ofScheme 4 gave(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide(57c) (340 mg, 0.708 mmol, 76% yield) as a white solid. 1H NMR (300 MHz,DMSO-d₆) δ 9.92 (s, 1H), 8.47-8.38 (m, 2H), 8.20-8.11 (m, 1H), 7.39-7.31(m, 2H), 7.20-7.11 (m, 2H), 3.93 (q, J=6.9 Hz, 1H), 3.70-3.56 (m, 1H),3.24 (s, 4H), 3.23-3.09 (m, 1H), 2.36-2.25 (m, 4H), 2.25-2.16 (m, 2H),1.11-1.02 (m, 2H), 0.69-0.57 (m, 1H), 0.39-0.30 (m, 2H), −0.01-−0.12 (m,2H).

Step-4: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxamide(57d)

Reaction of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide(57c) (340 mg, 0.708 mmol) in tetrahydrofuran/water (60 mL, 5:1) withphenyl 5-chloropyridin-2-ylcarbamate (13b) (167 mg, 0.672 mmol) usingpotassium carbonate (489 mg, 3.54 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel, 12 g eluting with CMA 80 in chloroform0-25%)(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxamide(57d) (35 mg, 0.055 mmol, 8.85% yield) as a free base, which wasconverted to hydrochloride salt in MeOH (10 mL) using HCl (3N in MeOH)(0.367 mL, 1.102 mmol) to obtain hydrochloride salt of compound 57d (34mg, 87% yield) as a solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.00 (s, 1H),9.67 (s, 3H), 9.45 (s, 1H), 8.84 (d, J=5.7 Hz, 2H), 8.37-8.21 (m, 1H),7.92-7.79 (m, 3H), 7.71 (d, J=5.8 Hz, 2H), 7.43 (d, J=1.6 Hz, 1H),7.41-7.35 (m, 1H), 7.34-7.23 (m, 1H), 4.85 (dd, J=9.2, 3.8 Hz, 1H), 4.02(q, J=12.1 Hz, 2H), 3.31 (s, 3H), 2.75-2.55 (m, 1H), 2.51 (m, 2H),2.47-2.30 (m, 1H), 1.30-0.99 (m, 2H), 0.68 (m, 1H), 0.43-0.29 (m, 2H),0.10-−0.05 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −75.82, −123.56;Optical rotation [α]_(D)=(+) 56.0 [0.05, MeOH].

Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-4-ethoxypyrrolidine-1,2-dicarboxamide(58j) Step-1: Preparation of(−)-N-(3-cyanobenzylidene)-2-methylpropane-2-sulfinamide (58a)

To a stirred solution of 3-formylbenzonitrile (45.4 g, 347 mmol) intetrahydrofuran (460 mL) was added(R)-2,4,6-triisopropylbenzenesulfinamide (35 g, 289 mmol),tetraisopropoxytitanium (173 mL, 578 mmol) and heated at reflux for 10h. Work up was performed as reported in step 1 of Scheme 1 to furnishafter column chromatography (silica gel 1.5 kg, eluting with 20% ethylacetate in hexane)(−)-N-(3-cyanobenzylidene)-2-methylpropane-2-sulfinamide (58a) (37.4 g,160 mmol, 55.3% yield) as a colorless solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.63 (s, 1H), 8.42 (dd, J=1.9, 1.3 Hz, 1H), 8.28 (dt, J=7.9, 1.4 Hz,1H), 8.07 (dt, J=7.7, 1.4 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H), 1.21 (s, 9H);MS (ES+) 257.2 (M+Na); Optical rotation: [α]_(D)=(−) 83.21 [2.55,CHCl₃].

Step-2: Preparation of(R)-N-((3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide(58b)

Compound 58b was prepared from(−)-N-(3-cyanobenzylidene)-2-methylpropane-2-sulfinamide (58a) (72 g,307 mmol) and 3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesiumbromide (1c) (430 mL, 430 mmol) as described in step 4 of Scheme 1 toafford(R)-N-((3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide(58b) (47.32 g, 137 mmol, 44.6% yield) thick yellow oil.

Step-3: Preparation of3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (58c)

To a stirred solution of(R)-N-((3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide(58b) (238.82 g, 691 mmol, ratio of diastereoisomers 55/45) in MTBE(1200 mL) was added hydrogen chloride in 1,4-Dioxane (363 mL, 1452 mmol)and stirred at room temperature for 7 h. Additional hydrogen chloride indioxane (346 mL, 1383 mmol) was added and stirred until all startingmaterial disappeared (24 h). The solid obtained was collected byfiltration washed with MTBE (2×250 mL), dried in air to furnish3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (58c) as an HCl salt(slightly hygroscopic); ¹H NMR (300 MHz, DMSO-d₆) δ 9.39-9.10 (m, 3H),7.57-7.49 (m, 2H), 7.45-7.34 (m, 3H), 7.26 (d, J=5.8 Hz, 1H), 7.15 (dd,J=8.0, 2.0 Hz, 1H), 5.58 (d, J=5.5 Hz, 1H); ¹⁹F NMR (282 MHz, DMSO) δ−129.75; MS (ES−) 240.2 (M−1). The above solid was dissolved in water(500 mL), basified by addition of NaOH (3N, 922 mL, 2765 mmol). Themixture was extracted with ethyl acetate (2×1000 mL). The organic layerswere combined washed with brine, dried, filtered and concentrated invacuum to furnish racemic3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (58c) (194 g, 804mmol, 116% yield) free base as a brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.38-7.35 (m, 2H), 7.30-7.24 (m, 2H), 6.86 (dd, J=11.5, 8.3 Hz, 1H),6.79 (dd, J=9.0, 2.2 Hz, 1H), 6.55 (ddd, J=8.3, 4.5, 2.2 Hz, 1H), 5.03(s, 2H), 4.94 (s, 1H), 2.13 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −138.23.

Step-4: Preparation of(+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (58d)

To a solution of racemic3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (58c) (ratio 55/45for two distereomers, 141.38 g, 586 mmol) in 85% tert-butanol (5600 mL,made from tert-butanol and water) was added D (−)-tartaric acid (88 g,586 mmol) and heated to 80° C. The clear solution was allowed to cool to29.8° C. (8 h). At this point the crystals obtained were collected byfiltration, washed with 200 mL of 85% tert-butanol, dried in vacuum toobtain (+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (58d)(36.4 g, 93 mmol, 15.87% overall yield) as a 2,3-dihydroxysuccinatesalt; MS (ES+) 225.2 (M+1); Chiral HPLC purity 96.077% ee. To(+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (58d)2,3-dihydroxysuccinate salt (18 g, 46.0 mmol) in 85% tert-butanol (388mL) was heated to 80° C. (internal temperature) until homogenous. Themixture was allowed to come to room temperature and the white crystalsformed were collected by filtration and air dried to afford pure(+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (58d) (16.7 g,42.7 mmol, 93% yield) 2,3-dihydroxysuccinate salt as a white solid; ¹HNMR (300 MHz, DMSO-d6) δ 7.90 (t, J=1.6 Hz, 1H), 7.78 (dt, J=7.6, 1.4Hz, 1H), 7.72 (dt, J=8.0, 1.4 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 6.99 (dd,J=11.5, 8.3 Hz, 1H), 6.74 (dd, J=8.7, 2.3 Hz, 1H), 6.59 (ddd, J=8.4,4.4, 2.3 Hz, 1H), 5.34 (s, 1H), 5.24 (s, 2H), 4.02 (s, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −135.95; MS (ES−) 240.2 (M−1); Chiral HPLCpurity >99.99%; Optical rotation: [α]_(D)=(+) 0.59 [1.025, MeOH].

Step-5: Preparation of(+)-3-((cyclopropylmethylamino)(3-(cyclopropylmethylamino)-4-fluorophenyl)methyl)benzonitrile(58e) and(+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile(58f)

To a stirred solution of(+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (58d) (8.321 g,34.5 mmol, which was converted to free base using aqueous NaOH andextracting with ethyl acetate) in MeOH (20 mL) was addedcyclopropanecarboxaldehyde (3.25 mL, 43.1 mmol) at 0° C. and stirred for30 mins. To this sodium borohydride (2.61 g, 69.0 mmol) was added andstirred at 0° C. for 1 hr. The reaction was concentrated in vacuum toremove methanol and residue was dissolved in ethyl acetate (200 mL),washed with water (2×50 mL), brine (50 mL), dried and concentrated. Thecrude residue was purified by flash column chromatography (silica gel120 g, eluting with ethyl acetate in hexanes 0-100%) to afford(+)-3-((cyclopropylmethylamino)(3-(cyclopropylmethylamino)-4-fluorophenyl)methyl)benzonitrile(58e) (1.087 g, 3.11 mmol, 9.02% yield) as a colorless syrup; ¹H NMR(300 MHz, DMSO-d₆) δ 7.88 (t, J=1.7 Hz, 1H), 7.75 (dt, J=7.9, 1.5 Hz,1H), 7.64 (dt, J=7.7, 1.4 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 6.90 (dd,J=11.9, 8.2 Hz, 1H), 6.84 (dd, J=8.9, 2.1 Hz, 1H), 6.57 (ddd, J=8.2,4.5, 2.0 Hz, 1H), 5.34 (td, J=6.0, 2.4 Hz, 1H), 4.81 (d, J=4.2 Hz, 1H),2.96 (t, J=6.3 Hz, 2H), 2.59 (m, 1H), 2.27 (m, 2H), 1.03 (m, 1H),0.98-0.84 (m, 1H), 0.40 (m, 4H), 0.26-0.17 (m, 2H), 0.05 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −137.04; MS (ES−) 348.4 (M−1); Opticalrotation: [α]_(D)=(+) 17.96 [0.245, MeOH]. followed by(+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile(58f) (7.891 g, 26.7 mmol, 77% yield) as colorless syrup; ¹H NMR (300MHz, DMSO-d₆) δ 7.84 (t, J=1.6 Hz, 1H), 7.71 (dt, J=7.9, 1.5 Hz, 1H),7.68-7.63 (m, 1H), 7.49 (t, J=7.7 Hz, 1H), 6.88 (dd, J=11.5, 8.3 Hz,1H), 6.81 (dd, J=9.0, 2.2 Hz, 1H), 6.56 (ddd, J=8.3, 4.5, 2.1 Hz, 1H),5.08 (s, 2H), 4.76 (d, J=2.8 Hz, 1H), 2.48 (m, 1H), 2.26 (m, 2H), 0.91(m, 1H), 0.42-0.34 (m, 2H), 0.09-0.01 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d6) δ −137.18; MS (ES+) 296.3 (M+1), (ES−) 294.3 (M−1); Opticalrotation: [α]_(D)=(+) 22.05 [0.88, CHCl₃].

Step-6: Preparation of(2R,4R)-1-(tert-butoxycarbonyl)-4-ethoxypyrrolidine-2-carboxylic acid(58g)

Alkylation of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(14b) (26 g, 112 mmol)) in THF (600 mL) with diethyl sulfate (34.7 g,225 mmol) using sodium hydride (60% dispersion in mineral oil, 27.0 g,675 mmol) as base according to the procedure reported in scheme 15 step1 gave (2R,4R)-1-(tert-butoxycarbonyl)-4-ethoxypyrrolidine-2-carboxylicacid (58g) (21.98 g, 85 mmol, 75% yield) as a white semisolid; ¹H NMR(300 MHz, DMSO-d₆) δ 12.45 (s, 1H), 4.20-4.05 (m, 1H), 4.00 (m, 1H),3.61-3.47 (m, 1H), 3.47-3.27 (m, 1H), 3.23-3.10 (m, 1H), 2.44-2.21 (m,1H), 2.02-1.85 (m, 2H), 1.39, 1.34 (2s, 9H, rotamers), 1.14-0.93 (m,3H); MS (ES+) 282.3 (M+Na); 258.3 (M−1)

Step-7: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-4-ethoxypyrrolidine-1-carboxylate(58h)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-ethoxypyrrolidine-2-carboxylic acid(58g) (676 mg, 2.61 mmol),(+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile(58f) (770 mg, 2.61 mmol) in tetrahydrofuran (20 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (645 mg, 2.61 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(2R,4R)-tert-butyl2-(5-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-4-ethoxypyrrolidine-1-carboxylate(58h) (1.21 gm, 86% yield) as a white solid, which was used as such fornext step

Step-8: Preparation of(2R,4R)-N-(5-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-4-ethoxypyrrolidine-2-carboxamide(58i)

Reaction of (2R,4R)-tert-butyl2-(5-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-4-ethoxypyrrolidine-1-carboxylate(58h) (590 mg, 1.099 mmol) in methanol (20 mL) using 3N HCl in methanol(1.832 mL, 5.50 mmol) followed by workup and purification as reported instep 6 of Scheme 4 gave(2R,4R)-N-(5-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-4-ethoxypyrrolidine-2-carboxamide(58i) (220 mg, 45.8% yield) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ10.09 (d, J=1.6 Hz, 1H), 8.34-8.21 (m, 1H), 7.85 (s, 1H), 7.77-7.67 (m,1H), 7.66 (m, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.23-7.09 (m, 2H), 4.90 (s,1H), 3.99-3.87 (m, 1H), 3.73 (t, J=6.1 Hz, 1H), 3.29 (q, J=7.0 Hz, 2H),3.02 (dd, J=10.5, 4.0 Hz, 1H), 2.86 (dd, J=11.0, 2.0 Hz, 1H), 2.62 (s,1H), 2.26 (d, J=6.1 Hz, 2H), 2.13-2.01 (m, 3H), 0.88 (m, 4H), 0.43-0.28(m, 2H), 0.12-−0.00 (m, 2H); MS (E+) 437.3 (M+1).

Step-9: Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-4-ethoxypyrrolidine-1,2-dicarboxamide(58j)

Reaction of(2R,4R)-N-(5-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-4-ethoxypyrrolidine-2-carboxamide(58i) (183 mg, 0.419 mmol) in tetrahydrofuran/water (10 mL, 5:1) withphenyl 5-chloropyridin-2-ylcarbamate (13b) (94 mg, 0.377 mmol) usingsodium bicarbonate (264 mg, 3.14 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel, 12 g eluting with CMA 80 in chloroform0-40%)(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-4-ethoxypyrrolidine-1,2-dicarboxamide(58j) (95 mg, 0.161 mmol, 43.6% yield) free base as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 9.45 (s, 1H), 9.16 (s, 1H), 8.30 (dd, J=2.6,0.7 Hz, 1H), 7.93-7.84 (m, 3H), 7.81 (dd, J=9.0, 2.6 Hz, 1H), 7.75-7.68(m, 1H), 7.66 (dt, J=7.6, 1.3 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.26-7.12(m, 2H), 4.89 (d, J=2.2 Hz, 1H), 4.58 (dd, J=9.0, 4.0 Hz, 1H), 4.17-4.06(m, 1H), 3.81-3.71 (m, 1H), 3.71-3.59 (m, 1H), 3.41 (q, J=7.0 Hz, 2H),2.66-2.57 (m, 1H), 2.25 (m, 2H), 2.16-2.04 (m, 1H), 1.04 (t, J=7.0 Hz,3H), 0.95-0.82 (m, 1H), 0.41-0.32 (m, 2H), 0.07-0.01 (m, 2H); ¹⁹F NMR(282 MHz, DMSO) δ −127.31; MS (ES+) 591.3 (M+1). The free base ofcompound 58j (83 mg, 0.140 mmol) was converted to hydrochloride salt inMeOH (5 mL) using HCl (3N in MeOH) (0.234 mL, 0.14 mmol) to obtainhydrochloride salt of compound 58j (80 mg, 91% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 10.42 (2s, 2H), 9.70 (s, 1H), 9.40 (s, 1H),8.30 (d, J=11.8 Hz, 2H), 8.18-7.99 (m, 2H), 7.99-7.81 (m, 3H), 7.65 (t,J=7.8 Hz, 1H), 7.39 (t, J=9.4 Hz, 1H), 6.68 (s, 2H), 5.77 (s, 1H),4.70-4.55 (m, 1H), 4.15 (s, 1H), 3.90-3.75 (m, 1H), 3.71-3.55 (m, 1H),3.42 (q, J=6.5 Hz, 2H), 2.71 (d, J=4.1 Hz, 2H), 2.47-2.35 (m, 1H), 2.06(m, 1H), 1.28-1.10 (m, 1H), 1.03 (t, J=6.8 Hz, 3H), 0.62-0.50 (m, 2H),0.36-0.25 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −124.07; MS (ES+) 591.3(M+1); Analysis calculated for C₃₁H₃₂ClFN₆O₃.1.7HCl.2H₂O: C, 54.03; H,5.51; Cl, 13.89; N, 12.20. Found: C, 53.71; H, 5.64; Cl, 13.58; N,11.88; Optical rotation [α]_(D)=(+) 73.14 [0.175, MeOH].

Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-cyclopropyl-4-hydroxypyrrolidine-1,2-dicarboxamide(59d) Step-1: Preparation of (R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-oxopyrrolidine-1-carboxylate(59a)

Reaction of (R)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylicacid (29a) (1.5 g, 6.54 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (2.55 g, 6.54 mmol) in tetrahydrofuran (50 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (1.651 g, 6.54 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-oxopyrrolidine-1-carboxylate(59a) (1.215 g, 2.022 mmol, 30.9% yield) as a light cream coloredcompound; ¹H NMR (300 MHz, DMSO-d₆) δ 10.08 (s, 1H), 8.57-8.45 (m, 2H),8.05-7.86 (m, 1H), 7.35-7.13 (m, 4H), 5.52 (s, 1H), 5.01-4.78 (m, 1H),3.88-3.71 (m, 2H), 3.17-2.99 (m, 1H), 2.68-2.55 (m, 2H), 2.49-2.39 (m,1H), 1.38 (2s, 9H, rotamers), 1.29-1.17 (m, 1H), 1.14 (s, 9H), 1.00-0.80(m, 1H), 0.72-0.56 (m, 1H), 0.42-0.28 (m, 2H), −0.03-−0.09 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −126.64, −126.84 (rotamers)

Step-2: Preparation of (2R,4S)-tert-butyl4-cyclopropyl-2-(5-((S)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(59b)

To a suspension of cerium (III) chloride (2.462 g, 9.99 mmol) intetrahydrofuran (40 mL) cooled to −78° C. was added dropwisecyclopropylmagnesium bromide (0.5M solution in THF, 18.64 mL, 9.32 mmol)maintaining internal temperature below −70° C. The reaction was stirredat −78° C. for 30 min followed by dropwise addition of a solution of(R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-oxopyrrolidine-1-carboxylate(59a) (1 g, 1.665 mmol) in THF maintaining internal temperature below−70° C. during addition. The reaction mixture was warmed to 0° C. over 2h, diluted with ethyl acetate (50 mL) and filtered to remove insolublematerial. The filtrate was diluted with water and organic layer wasseparated, washed with brine, dried, filtered and concentrated in vacuumto furnish (2R,4S)-tert-butyl4-cyclopropyl-2-(5-((S)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(59b) which was used as such in next step without purification.

Step-3: Preparation of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-cyclopropyl-4-hydroxypyrrolidine-2-carboxamide(59c)

Reaction of crude (2R,4S)-tert-butyl4-cyclopropyl-2-(5-((S)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(59b) obtained from step 2 above in methanol (10 mL) using 3N HCl inmethanol (15 mL) followed by workup and purification as reported in step6 of Scheme 4 gave after purification by flash column chromatography(silica gel, eluting with 0-60% CMA-80 in CHCl₃)(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-cyclopropyl-4-hydroxypyrrolidine-2-carboxamide(59c) (163 mg, 22.33% yield for two steps), MS (439.5, M+1).

Step-4: Preparation of(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-cyclopropyl-4-hydroxypyrrolidine-1,2-dicarboxamide(59d)

Reaction of(2R,4S)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-cyclopropyl-4-hydroxypyrrolidine-2-carboxamide(59c) (160 mg, 0.365 mmol) in tetrahydrofuran/water (10 mL, 5:1) withphenyl 5-chloropyridin-2-ylcarbamate (13b) (82 mg, 0.328 mmol) usingsodium hydrogen carbonate (184 mg, 2.189 mmol) as base according toprocedure reported in step 3 of Scheme 13 gave after purification byflash column chromatography (silica gel, 12 g eluting with 9:1 ethylacetate/methanol in hexane 0-50%)(2R,4S)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-cyclopropyl-4-hydroxypyrrolidine-1,2-dicarboxamide(59d) as a free base which was converted to hydrochloride salt (3N HClin MeOH) to give compound 59d (25 mg, 0.042 mmol, 12.84% yield)hydrochloride salt as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.94(s, 1H), 9.83 (s, 2H), 9.31 (s, 1H), 8.96 (d, J=6.0 Hz, 2H), 8.31 (d,J=2.0 Hz, 1H), 8.12 (d, J=5.2 Hz, 1H), 7.99-7.88 (m, 2H), 7.88-7.76 (m,2H), 7.46-7.32 (m, 1H), 4.68-4.60 (m, 3H), 3.63 (d, J=10.5 Hz, 1H), 3.50(d, J=10.3 Hz, 1H), 2.57 (m, 2H), 2.28 (m, 1H), 1.95 (m, 1H), 1.32-1.19(m, 1H), 1.15-0.94 (m, 2H), 0.82-0.61 (m, 1H), 0.47-0.20 (m, 5H),0.13-−0.02 (m, 4H); ¹⁹F NMR (282 MHz, DMSO) δ −124.96; MS (ES+): 593.6(M+1); Optical rotation [α]_(D)=(+) 102.6 [0.15, MeOH].

Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((R)-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(60a)

Reaction of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1o) (0.14 g, 0.5 mmol),(+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile (58f) (0.15 g, 0.5 mmol) in tetrahydrofuran (5 mL) usingethyl 2-ethoxyquinoline-1(2H)-carboxylate (0.12 g, 0.5 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash chromatography (silica gel 24 g, elutingwith CMA80 in chloroform 0 to 30%)(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((R)-(3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(60a) (96 mg, 34% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.65 (s, 1H), 8.51 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.69 (m 2H),7.58-7.45 (m, 2H), 7.30-7.24 (m, 2H), 7.20 (m, 3H), 5.31 (d, J=4.8 Hz,1H), 4.91 (s, 1H), 4.51 (dd, J=9.0, 4.7 Hz, 1H), 4.34 (q, J=4.8 Hz, 1H),3.69 (m, 1H), 3.48 (m, 1H), 2.44-2.32 (m, 1H), 2.27 (s, 2H), 1.90 (m,1H), 1.03-0.78 (m, 1H), 0.49-0.29 (m, 2H), 0.10-0.02 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −128.01; MS (ES+) 562.4 (M+1), 584.4 (M+Na), (ES−)596.5, 598.4 (M+Cl); Optical rotation [α]_(D)=(+) 83.49 [0.355, MeOH].

Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(61b) Step-1: Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(61a)

Reaction of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1o) (0.28 g, 1.0 mmol),(S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide(31e) (0.39 g, 1.0 mmol) in tetrahydrofuran (10 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.25 g, 1.0 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash chromatography (silica gel 24 g, elutingwith CMA80 in chloroform 0 to 30%)(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(61a) (0.43 g, 65%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.83(s, 1H), 8.78-8.64 (m, 2H), 8.41-8.27 (m, 1H), 7.99-7.86 (m, 1H),7.80-7.67 (m, 2H), 7.52-7.41 (m, 3H), 7.41-7.31 (m, 1H), 7.28 (d, J=8.1Hz, 1H), 7.22 (m, 1H), 6.35 (s, 1H), 5.49 (d, J=4.6 Hz, 1H), 4.70 (dd,J=9.0, 4.6 Hz, 1H), 4.54 (d, J=4.6 Hz, 1H), 3.87 (dd, J=10.1, 5.2 Hz,1H), 3.73-3.60 (m, 1H), 2.76 (m, 2H), 2.62-2.47 (m, 1H), 2.16-2.01 (m,1H), 1.29 (s, 9H), 1.04 (m, 2H), 0.75 (m, 1H), 0.49 (m, 2H), 0.01 (m,2H); MS (ES+) 656.5 (M+1), 678.5 (M+Na).

Step-2: Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(61b)

Reaction of crude(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(61a) (0.13 g, 0.2 mmol) in ethanol (5 mL) using conc. HCl (0.12 mL)followed by workup and purification as reported in step 6 of Scheme 4gave after purification by flash column chromatography (silica gel 24 g,eluting with 0-30% CMA-80 in chloroform)(2R,4R)-N1-(4-chlorophenyl)-N2-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(61b) (95 mg, 86% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.56 (s, 1H), 8.55-8.42 (m, 2H), 8.07 (dd, J=7.9, 2.2 Hz, 1H), 7.69 (td,J=7.7, 1.9 Hz, 1H), 7.62-7.47 (m, 3H), 7.32-7.22 (m, 2H), 7.22-7.12 (m,2H), 7.08 (dd, J=10.5, 8.7 Hz, 1H), 5.30 (d, J=4.9 Hz, 1H), 4.49 (dd,J=9.0, 4.7 Hz, 1H), 4.33 (d, J=5.0 Hz, 1H), 3.68 (dd, J=10.1, 5.2 Hz,1H), 3.50-3.42 (m, 1H), 2.40-2.21 (m, 5H), 1.89 (m, 1H), 1.03 (m, 2H),0.60 (m, 1H), 0.39-0.27 (m, 2H), −0.03-−0.13 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −129.58; MS (ES+) 552.5 (M+), MS (ES−) 586.4 (M+Cl); Opticalrotation [α]_(D)=(+) 91.1 [0.18, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide(62c) Step-1: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(62a)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(14b) (0.15 g, 0.65 mmol),(S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-methylpropane-2-sulfinamide(31e) (0.25 g, 0.65 mmol) in tetrahydrofuran (50 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.175 g, 0.71 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(62a) (0.24 g, 61%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.71(s, 1H), 8.57-8.48 (m, 1H), 7.97 (d, J=7.4 Hz, 1H), 7.80-7.66 (m, 1H),7.33-6.97 (m, 4H), 6.14 (s, 1H), 5.33-5.15 (m, 1H), 4.23 (m, 2H),3.55-3.41 (m, 1H), 3.27-3.14 (m, 1H), 2.65-2.53 (m, 2H), 2.41-2.29 (m,1H), 1.78 (m, 1H), 1.44-1.13 (m, 11H), 1.09 (s, 9H), 0.65-0.44 (m, 1H),0.38-0.23 (m, 2H), −0.13-−0.27 (m, 2H); MS (ES+) 603.6 (M+1), MS (ES−)601.6 (M−1).

Step-2: Preparation of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(62b)

Reaction of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(62a) (0.24 g, 0.4 mmol) in methanol (5 mL) using conc HCl followed byworkup and purification as reported in step 6 of Scheme 4 gave(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(62b) as a yellow oil, which was used as such in next step withoutfurther purification.

Step-3: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide(62c)

Reaction of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(62b) obtained in above step 2 in tetrahydrofuran/water (20 mL/1 mL)with phenyl 5-chloropyridin-2-ylcarbamate (13b) (0.09 g, 0.35 mmol)using sodium bicarbonate (0.33 g, 4 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel 12 g, eluting with CMA-80 in chloroform0-30%)(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide(62c) (0.11 g, 50%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.63(s, 1H), 9.16 (s, 1H), 8.50-8.43 (m, 1H), 8.32-8.26 (m, 1H), 8.08-8.00(m, 1H), 7.88 (dd, J=9.0, 0.8 Hz, 1H), 7.79 (dd, J=9.0, 2.7 Hz, 1H),7.74-7.64 (m, 1H), 7.52 (dt, J=8.0, 1.0 Hz, 1H), 7.22-7.02 (m, 2H), 5.30(d, J=5.0 Hz, 1H), 4.60-4.47 (m, 1H), 4.36-4.23 (m, 1H), 3.78-3.64 (m,1H), 3.58-3.42 (m, 2H), 2.40-2.19 (m, 5H), 1.88 (m, 1H), 1.10-0.92 (m,2H), 0.70-0.51 (m, 1H), 0.40-0.25 (m, 2H), −0.04-−0.17 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −129.34; MS (ES+) 553.4 (M+1), MS (ES−) 551.3(M−1); Optical rotation [α]_(D)=(+) 74.44 [0.36, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(63g) Step: 1 Preparation of (E)-4-(3-cyclopropylacryloyl)benzonitrile(63b)

To a stirred solution of 4-acetylbenzonitrile (63a) (5 g, 34.4 mmol) inethanol (100 mL) at 0° C. was added cyclopropanecarboxaldehyde (4.15 mL,55.1 mmol) followed by potassium hydroxide (2M aqueous solution, 3.44mL, 6.89 mmol). The reaction mixture allowed to attain room temperatureand stirred for 24 h. The reaction was acidified with HCl to pH 6 andconcentrated in vacuum maintaining bath temperature below 35° C. Theresidue obtained was purified by flash column chromatography (silica geleluting with ethyl acetate in hexanes 0 to 20%) to afford(E)-4-(3-cyclopropylacryloyl)benzonitrile (63b) (512 mg, 2.60 mmol,7.54% yield) as a colorless liquid; ¹H NMR (300 MHz, DMSO-d₆) δ8.12-8.08 (m, 2H), 8.02-7.99 (m, 2H), 7.25 (d, J=15.0 Hz, 1H), 6.57 (dd,J=15.1, 10.4 Hz, 1H), 1.80 (dddd, J=12.4, 10.4, 7.9, 4.5 Hz, 1H),1.08-0.99 (m, 2H), 0.79 (tt, J=4.8, 2.4 Hz, 2H); MS (ES−) 196.1 (M−1).

Step 2: Preparation of 4-(3-cyclopropylpropanoyl)benzonitrile (63c)

To a stirred solution of (E)-4-(3-cyclopropylacryloyl)benzonitrile (63b)(1.1 g, 5.58 mmol) in acetonitrile (10 mL) was added tri-n-butyltinhydride (1.489 mL, 5.58 mmol) and heated at reflux for 6 h. The reactionmixture was cooled to room temperature and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica geleluting with ethyl acetate in hexanes 0 to 100%) to afford4-(3-cyclopropylpropanoyl)benzonitrile (63c) (457 mg, 2.294 mmol, 41.1%yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.08-8.03 (m,2H), 7.98-7.91 (m, 2H), 3.09 (t, J=7.2 Hz, 2H), 1.46 (q, J=7.1 Hz, 2H),0.77-0.59 (m, 1H), 0.38-0.26 (m, 2H), 0.06-−0.04 (m, 2H); MS (ES−) 198.2(M−1).

Step-3: Preparation of(+)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(63d)

Compound (63d) was prepared from 4-(3-cyclopropylpropanoyl)benzonitrile(63c) (0.814 g, 4.08 mmol) and (R)-2-methylpropane-2-sulfinamide (0.45g, 3.71 mmol), using procedure as reported in step 3 of scheme 31 toafford(+)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(63d) (720 mg, 2.38 mmol, 64.1% yield) as a light yellow syrup; ¹H NMR(300 MHz, DMSO-d₆) δ 8.11-7.93 (m, 4H), 3.34 (m, 2H), 1.44 (m, 1H), 1.24(s, 10H), 0.73 (m, 1H), 0.45-0.29 (m, 2H), 0.03 (m, 2H); Opticalrotation: [α]_(D)=(+) 16.55 [0.29, MeOH].

Step-4: Preparation of(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(63e)

Compound (63e) was prepared from(+)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide(63d) (0.5 g, 1.653 mmol), using procedure as reported in step 4 ofscheme 31 to afford(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(63e) (538 mg, 1.301 mmol, 79% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.83-7.66 (m, 2H), 7.61-7.44 (m, 2H), 6.90 (dd, J=11.3, 8.5Hz, 1H), 6.70 (dd, J=8.7, 2.4 Hz, 1H), 6.47 (ddd, J=8.6, 4.3, 2.4 Hz,1H), 5.27 (s, 1H), 5.11 (s, 2H), 2.62-2.55 (m, 1H), 2.46-2.39 (m, 1H),1.12 (s, 9H), 1.06 (s, 1H), 0.99-0.80 (m, 1H), 0.64 (s, 1H), 0.36 (m,2H), −0.02-−0.14 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −137.54; MS (ES+)414.396 (M+1); Optical rotation: [α]_(D)=(−) 83.24 [0.185, MeOH].

Step-5: Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(1-(4-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(63f)

Reaction of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1o) (0.14 g, 0.5 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide(63e) (0.2 g, 0.5 mmol) in tetrahydrofuran (10 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.12 g, 0.5 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash chromatography (silica gel 24 g, elutingwith CMA80 in chloroform 0 to 30%)(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(1-(4-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(63f) (0.13 g, 38%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.85(s, 1H), 8.71 (s, 1H), 8.28 (d, J=7.5 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H),7.80-7.64 (m, 4H), 7.48 (dd, J=8.9, 2.3 Hz, 2H), 7.38 (t, J=9.8 Hz, 1H),7.28 (s, 1H), 5.68 (s, 1H), 5.52 (d, J=4.6 Hz, 1H), 4.71 (dd, J=9.2, 4.6Hz, 1H), 4.54 (d, J=4.8 Hz, 1H), 3.88 (dd, J=9.9, 5.2 Hz, 1H), 3.70 (d,J=10.0 Hz, 1H), 2.79 (m, 1H), 2.61 (m, 1H), 1.42 (m, 2H), 1.33 (s, 9H),1.14-0.98 (m, 2H), 0.83 (m, 1H), 0.54 (m, 2H), 0.17-0.04 (m, 2H); MS(ES+) 680.5 (M+1), 702.5 (M+Na), MS (ES−) 678.6 (M−1), 714.5 (M+Cl).

Step-6: Preparation of(2R,4R)-N2-(5-((+)-1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(63g)

Reaction of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(1-(4-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(63f) (0.13 g, 0.2 mmol) in ethanol (5 mL) using conc. HCl (0.12 mL)followed by workup and purification as reported in step 6 of Scheme 4gave after purification by flash column chromatography (silica gel 24 g,eluting with 0-30% CMA-80 in chloroform)(2R,4R)-N2-(5-((+)-1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(63g) (70 mg, 61% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.60 (s, 1H), 8.50 (s, 1H), 8.10-7.96 (m, 1H), 7.78-7.67 (m, 2H),7.61-7.52 (m, 4H), 7.30-7.24 (m, 2H), 7.14-7.08 (m, 2H), 5.30 (d, J=4.9Hz, 1H), 4.48 (td, J=9.2, 4.0 Hz, 1H), 4.33 (q, J=4.8 Hz, 1H), 3.68 (dd,J=10.0, 5.4 Hz, 1H), 3.50-3.41 (m, 1H), 2.23 (m, 5H), 1.95-1.83 (m, 1H),1.13-0.91 (m, 2H), 0.80-0.53 (m, 1H), 0.40-0.27 (m, 2H), −0.04-−0.13 (m,2H).19F NMR (282 MHz, DMSO-d₆) δ −129.19; MS (ES+) 598.5 (M+Na), (ES−)574.4 (M−1), 610.4 (M+Cl); Optical rotation: [α]_(D)=(+) 81.7 [0.225,CH₃OH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(64g) Step-1: Preparation of(E)-3-cyclopropyl-1-(pyridin-3-yl)prop-2-en-1-one (64b)

To a stirred solution of 3-acetylpyridine (64a) (9.07 mL, 83 mmol) inmethanol (200 mL) cooled to 0° C. was added cyclopropanecarboxaldehyde(9.95 mL, 132 mmol) and aqueous potassium hydroxide (1N solution, 16.51mL, 16.51 mmol). The reaction was allowed to warm to room temperatureovernight. The reaction was acidified with 1N hydrochloric acid andconcentrated in vacuum to remove methanol. The crude residue wasdissolved in ethyl acetate (300 mL) washed with sodium carbonatesolution, water (2×100 mL), brine (50 mL), dried, filtered andconcentrated in vacuum. The crude residue was purified by flash columnchromatography (silica gel, 80 g, eluting with ethyl acetate in hexanes0 to 100%) to afford (E)-3-cyclopropyl-1-(pyridin-3-yl)prop-2-en-1-one(64b) (5.99 g, 41.9%); ¹H NMR (300 MHz, DMSO-d6) δ 9.14 (td, J=2.7, 0.9Hz, 1H), 8.80 (ddd, J=4.9, 3.3, 1.7 Hz, 1H), 8.36-8.27 (m, 1H), 7.57(ddt, J=8.0, 4.8, 1.2 Hz, 1H), 7.28 (d, J=15.1 Hz, 1H), 6.58 (dd,J=15.1, 10.3 Hz, 1H), 1.80 (dddd, J=12.5, 10.4, 7.8, 4.5 Hz, 1H),1.08-0.99 (m, 2H), 0.85-0.76 (m, 2H); MS (ES+) 196.1 (M+Na).

Step-2: Preparation of 3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (64c)

To a stirred solution of(E)-3-cyclopropyl-1-(pyridin-3-yl)prop-2-en-1-one (64b) (5.93 g, 34.2mmol) in benzene (150 mL) was added tributylstannane (18.42 mL, 68.5mmol) and heated to reflux. The reaction was stirred at reflux for 5 hand cooled to room temperature. Benzene was evaporated and the residuewas purified by flash column chromatography (silica gel, 80 g, elutingwith ethyl acetate in hexanes 0 to 100%) to afford3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (64c) (5.29 g, 88%); ¹H NMR(300 MHz, DMSO-d₆) δ 9.07 (dd, J=2.3, 0.9 Hz, 1H), 8.72 (dd, J=4.8, 1.7Hz, 1H), 8.24 (ddd, J=8.0, 2.4, 1.8 Hz, 1H), 7.50 (ddd, J=8.0, 4.9, 0.9Hz, 1H), 3.09 (t, J=7.2 Hz, 2H), 1.47 (q, J=7.1 Hz, 2H), 0.70 (dddd,J=12.0, 8.1, 5.1, 2.2 Hz, 1H), 0.40-0.21 (m, 2H), 0.06-−0.05 (m, 2H).

Step-3: Preparation of(−)-N-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2-sulfinamide(64d)

Compound (64d) was prepared from3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (64c) (3.98 g, 22.69 mmol)and (R)-2-methylpropane-2-sulfinamide (2.5 g, 20.63 mmol) usingprocedure as reported in step 3 of Scheme 31 to afford(−)-N-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2-sulfinamide(64d) (2.5 g, 8.98 mmol, 43.5% yield) as a yellow syrup; ¹H NMR (300MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.72 (dd, J=4.8, 1.6 Hz, 1H), 8.24 (d,J=8.1 Hz, 1H), 7.53 (dd, J=8.1, 4.8 Hz, 1H), 3.40 (m, 1H), 3.30 (m, 1H),1.47 (q, J=7.4 Hz, 2H), 1.24 (s, 9H), 0.82-0.66 (m, 1H), 0.44-0.29 (m,2H), 0.12-0.01 (m, 2H); Optical Rotation [α]_(D)=(−) 17.29 [0.59,MeOH].

Step-4: Preparation of(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide(64e)

To a stirred solution of(−)-N-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2-sulfinamide(64d) (82 g, 295 mmol) in Toluene (1700 mL) at −20° C. was addeddropwise a freshly prepared solution of(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (1c) (920mL, 736 mmol) over a period of 120 mins. The reaction mixture wasstirred at −20° C. for 1 h and quenched with 1N aqueous KHSO₄ (1600 mL).The reaction mixture was stirred for 1 h at room temperature, basifiedwith 2N NaOH to pH˜8 and extracted with ethyl acetate (1500, 700 mL).The organic layers were combined washed with water (2×700 mL), brine(700 mL), dried and concentrated in vacuum. The crude residue waspurified by flash column chromatography (silica gel, eluting with (9:1)ethyl acetate/methanol in hexanes 0 to 50%) to afford(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide(64e) (54.155 g, 139 mmol, 47.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.53-8.48 (m, 1H), 8.39 (dd, J=4.7, 1.5 Hz, 1H), 7.70(dt, J=8.1, 2.0 Hz, 1H), 7.32 (dd, J=8.0, 4.7 Hz, 1H), 6.90 (dd, J=11.2,8.5 Hz, 1H), 6.73 (dd, J=8.8, 2.4 Hz, 1H), 6.56-6.45 (m, 1H), 5.26 (s,1H), 5.10 (s, 2H), 2.67-2.54 (m, 2H), 1.28-1.11 (m, 1H), 1.12 (s, 9H),0.91 (m, 1H), 0.64 (m, 1H), 0.40-0.30 (m, 2H), −0.02-−0.14 (m, 2H); 19FNMR (282 MHz, DMSO d₆) δ −137.67; MS (ES+) 390.4 (M+1); (ES−) 388.4(M−1); Optical Rotation [α]_(D)=(−) 105.71 [0.28, MeOH].

Step-5: Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(64f)

Reaction of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1o) (0.14 g, 0.5 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide(64e) (0.2 g, 0.5 mmol) in tetrahydrofuran (5 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.12 g, 0.5 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash chromatography (silica gel 24 g, elutingwith CMA80 in chloroform 0 to 30%)(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(64f) (0.09 g, 27%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.97(s, 1H), 8.83 (d, J=2.5 Hz, 2H), 8.72 (dd, J=4.5, 2.8 Hz, 1H), 8.40 (d,J=7.4 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.92-7.81 (m, 2H), 7.70-7.56 (m,3H), 7.54-7.38 (m, 2H), 5.81 (s, 1H), 5.64 (d, J=4.5 Hz, 1H), 4.82 (d,J=8.6 Hz, 1H), 4.66 (m, 1H), 3.99 (m, 1H), 3.82 (d, J=10.1 Hz, 1H),2.42-2.32 (m, 3H), 2.23 (m, 1H), 1.45 (m, 10H), 1.31-1.10 (m, 1H), 0.96(s, 1H), 0.65 (s, 2H), 0.33-0.24 (m, 2H); MS (ES+) 656.5 (M+1), 678.5(M+Na), MS (ES−) 654.4 (M−1), 690.5 (M+Cl).

Step-6: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(64g)

Reaction of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(64f) (0.08 g, 0.12 mmol) in ethanol (4 mL) using conc. HCl (0.12 mL)followed by workup and purification as reported in step 6 of Scheme 4gave after purification by flash column chromatography (silica gel 24 g,eluting with 0-30% CMA-80 in chloroform)(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(64g) (35 mg, 50% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.61 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.50 (s, 1H), 8.35 (dd, J=4.7, 1.5Hz, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.73 (dt, J=8.1, 2.0 Hz, 1H), 7.58-7.49(m, 2H), 7.32-7.23 (m, 3H), 7.18-7.09 (m, 2H), 5.30 (d, J=4.9 Hz, 1H),4.50 (dd, J=9.0, 4.7 Hz, 1H), 4.33 (d, J=5.0 Hz, 1H), 3.68 (dd, J=10.0,5.3 Hz, 1H), 3.49 (s, 1H), 2.38 (m, 3H), 2.23 (m, 1H), 1.03 (m, 2H),0.64 (m, 1H), 0.41-0.27 (m, 2H), −0.03-−0.13 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −129.28; MS (ES+) 552.5 (M+1), 574.5, 576.5 (M+Na), (ES−)550.5, 552.4 (M−1), 586.5, 588.5 (M+Cl); Optical rotation: [α]_(D)=(+)68.0 [0.25, CH₃OH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(65b) Step-1: Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(65a)

Reaction of(2R,4R)-N-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(37b) (0.1 g, 0.19 mmol), 4-Chlorophenyl isocyanate (0.045 g, 0.3 mmol)using TEA (80 μL) as base in THF (5 mL) according to the procedurereported in step 9 of Scheme 1 gave after purification by flash columnchromatography(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(65a) (0.105 g, 80%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.48(s, 1H), 8.57-8.47 (m, 2H), 8.04-7.94 (m, 1H), 7.73 (td, J=7.7, 1.7 Hz,1H), 7.54 (d, J=8.9 Hz, 2H), 7.27 (dd, J=10.5, 7.5 Hz, 3H), 7.23-7.05(m, 2H), 6.14 (s, 1H), 4.53 (dd, J=9.2, 3.9 Hz, 1H), 4.06 (s, 1H),3.78-3.55 (m, 2H), 3.21 (s, 3H), 2.68-2.52 (m, 2H), 2.42-2.24 (m, 1H),2.15-2.02 (m, 1H), 1.21 (m, 1H), 1.09 (s, 9H), 0.91-0.65 (m, 2H),0.62-0.47 (m, 1H), 0.29 (m, 2H), −0.16-−0.21 (m, 2H); MS (ES+) 670.5(M+1), 692.5 (M+Na), MS (ES−) 668.5 (M−1), 704.5 (M+Cl).

Step 2: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(65b)

Reaction of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(65a) (0.1 g, 0.43 mmol) in ethanol (5 mL) using conc. HCl (0.12 mL) asreported in step 6 of Scheme 4 gave after purification by flash columnchromatography (silica gel 12 g, eluting with CMA80 in chloroform 0 to30%)(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(65b) (65 mg, 65% yield) hydrochloride salt as white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.65 (s, 1H), 8.90 (s, 3H), 8.69-8.64 (m, 1H), 8.57 (s,1H), 7.99 (dd, J=7.4, 2.5 Hz, 1H), 7.87 (td, J=7.8, 1.8 Hz, 1H),7.61-7.52 (m, 2H), 7.47-7.41 (m, 1H), 7.38-7.25 (m, 4H), 7.17-7.08 (m,1H), 4.55 (dd, J=9.2, 4.2 Hz, 1H), 4.15-4.04 (m, 1H), 3.75 (dd, J=10.5,5.3 Hz, 1H), 3.61 (dd, J=10.4, 3.5 Hz, 1H), 3.23 (s, 3H), 2.52-2.33 (m,3H), 2.14-2.00 (m, 1H), 1.10 (m, 2H), 0.67 (m, 1H), 0.45-0.34 (m, 2H),−0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −125.63; MS (ES+) 566.5(M+1), (ES−) 600.5 (M+Cl); Optical rotation: [α]_(D)=(+) 94.4 [0.25,MeOH].

Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(66c) Step 1: Preparation of (2R,4R)-benzyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(66a)

Reaction of(2R,4R)-1-(benzyloxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(15b) (2 g, 7.16 mmol),(R)-N-((−)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide(1e) (2.41 g, 7.52 mmol) in tetrahydrofuran (50 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (1.86 g, 7.52 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gaveafter purification by flash column chromatography (silica gel 40 g,eluting with CMA 80 in chloroform 0 to 100%) (2R,4R)-benzyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(66a) (3.11 g, 75%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.54(2s, 1H, rotamers), 7.81 (m, 1H), 7.45-7.09 (m, 12H), 6.00 (s, 1H), 5.47(s, 1H), 5.17-4.93 (m, 2H), 4.44 (m, 1H), 3.99 (m, 1H), 3.69 (m, 1H),3.50-3.36 (m, 1H), 3.18 (m, 3H), 2.11-1.98 (m, 2H), 1.13 (s, 9H); MS(ES+) 582.5 (M+1).

Step 2: Preparation of(2R,4R)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(66b)

Debenzylation by hydrogenation of (2R,4R)-benzyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(66a) (3.0 g, 5.15 mmol) in ethanol (50 mL), using palladium on carbon10% (0.3 g) as catalyst according to procedure reported in step 2 ofScheme 13 gave(2R,4R)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(66b) (1.45 g, 63% yield) as a white solid; MS (ES+) 448.4 (M+1), (ES−)446.3 (M−1).

Step-3: Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(66c)

Reaction of(2R,4R)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(66b) (0.18 g, 0.4 mmol) in tetrahydrofuran (20 mL), phenyl(5-chloropyridin-2-yl)carbamate (13b) (0.13 g, 0.52 mmol), usingtriethylamine (0.08 g, 0.8 mmol) as base using reaction and workupconditions as reported in step 3 of Scheme 13 gave(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(66c) (0.12 g, 52% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.78 (s, 1H), 9.45 (s, 1H), 8.60 (m, 1H), 8.25-8.03 (m, 3H), 7.72-7.43(m, 7H), 6.29 (d, J=5.6 Hz, 1H), 5.77 (d, J=5.4 Hz, 1H), 4.88 (d, J=8.3Hz, 1H), 4.34 (m, 1H), 4.02 (m, 2H), 3.50 (s, 3H), 2.75-2.59 (m, 1H),2.39 (m, 1H), 1.42 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.17; MS(ES+) 624.5, 626.4 (M+Na), (ES−) 601.5.5, 602.5 (M−1); Optical rotation[α]_(D)=(+) 22.22 [0.135, MeOH].

Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(ethylamino)-1-phenylpropyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(67b) Step-1: Preparation of(2R,4R)-N2-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(67a)

Reaction of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(66c) (0.8 g, 1.3 mmol) in ethanol (50 mL) using conc. HCl (1 mL) asreported in step 6 of Scheme 4 gave after purification by flash columnchromatography (silica gel 12 g, eluting with CMA80 in chloroform 0 to40%)(2R,4R)-N2-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(67a) (0.32 g, 49%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.44(s, 1H), 9.13 (s, 1H), 8.36-8.24 (m, 1H), 7.96-7.74 (m, 3H), 7.43-7.32(m, 2H), 7.32-7.21 (m, 2H), 7.21-7.10 (m, 3H), 5.06 (s, 1H), 4.57 (d,J=8.2 Hz, 1H), 4.04 (s, 1H), 3.73 (m, 2H), 3.21 (m, 3H), 2.45-2.28 (m,3H), 2.09 (m, 1H); 19F NMR (282 MHz, DMSO-d₆) δ −128.12; MS(ES+) 498.4(M+1); MS (ES−) 532.4 (M+Cl).

Step 2: Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(ethylamino)-1-phenylpropyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(67b)

Reductive amination of(2R,4R)-N2-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(67a) (0.075 g, 0.15 mmol) in MeOH (3 mL) using acetaldehyde (0.02 g,0.45 mmol) and sodium borohydride (0.017 g, 0.45 mmol) according to theprocedure reported in Scheme 41 gave after workup and purification byflash column chromatography (silica gel 12 g, eluting with methanol inchloroform 0 to 10%)(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(ethylamino)-1-phenylpropyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(67b) (0.055 g, 69% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.51-9.42 (s, 1H), 9.16 (s, 1H), 8.30 (dd, J=2.7, 0.8 Hz, 1H), 7.94-7.85(m, 2H), 7.81 (dd, J=9.0, 2.6 Hz, 1H), 7.38 (d, J=7.0 Hz, 2H), 7.27 (t,J=7.5 Hz, 2H), 7.22-7.09 (m, 4H), 4.76 (s, 1H), 4.58 (dd, J=9.2, 4.0 Hz,1H), 4.09-3.97 (m, 2H), 3.84-3.63 (m, 1H), 3.22 (s, 3H), 2.46-2.27 (m,3H), 2.09 (m, 1H), 1.03 (t, J=6.9 Hz, 3H); 19F NMR (282 MHz, DMSO-d₆) δ−128.09; MS(ES+) 526.4 (M+1), 548.4 (M+Na) MS (ES−) 524.4 (M−1), 560.4(M+Cl); Optical rotation: [α]_(D)=(+) 72.31 [0.26, MeOH].

Preparation of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(68a)

Reaction of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid (0.095 g, 0.03 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (0.13 g, 0.3 mmol) in tetrahydrofuran (5 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.085 g, 0.3 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(68a) (0.04 g, 21%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.67(s, 1H), 8.56-8.44 (m, 3H), 8.09 (d, J=7.4 Hz, 1H), 7.61-7.48 (m, 2H),7.34-7.24 (m, 4H), 7.24-7.14 (m, 1H), 7.10 (m, 1H), 5.51 (s, 1H), 5.33(d, J=4.4 Hz, 1H), 4.51 (dd, J=9.1, 4.7 Hz, 1H), 4.34 (m, 1H), 3.68 (m,1H), 3.54-3.45 (m, 1H), 2.42-2.27 (m, 3H), 1.25-1.16 (m, 1H), 1.14 (s,9H), 0.89 (m, 1H), 0.63 (m, 1H), 0.34 (m, 2H), −0.07 (m, 2H); 19F NMR(282 MHz, DMSO-d₆) δ −128.49; MS (ES+) 656.5 (M+1), 678.5, 680.5 (M+Na)(ES−) 654.5, 655.5 (M−1), 690.5, 692.6 (M+Cl).

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(69a)

Reaction of(2R,4R)-N1-(4-chlorophenyl)-N2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(68a) (0.17 g, 0.26 mmol) in methanol (5 mL) using 3M HCl in methanol asreported in step 6 of Scheme 4 gave after purification by flash columnchromatography (silica gel 12 g, eluting with CMA80 in chloroform 0 to40%)(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-hydroxypyrrolidine-1,2-dicarboxamide(69a) (0.1 g, 70%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.61(s, 1H), 8.50 (s, 1H), 8.47-8.40 (m, 2H), 8.05 (d, J=7.7 Hz, 1H),7.59-7.49 (m, 2H), 7.38-7.31 (m, 2H), 7.31-7.23 (m, 2H), 7.13 (d, J=8.1Hz, 2H), 5.30 (d, J=4.8 Hz, 1H), 4.50 (dd, J=9.0, 4.7 Hz, 1H), 4.40-4.26(m, 1H), 3.68 (dd, J=10.0, 5.3 Hz, 1H), 3.51-3.41 (m, 1H), 2.39-2.12 (m,5H), 1.96-1.81 (m, 1H), 1.12-0.92 (m, 2H), 0.72-0.54 (m, 1H), 0.41-0.26(m, 2H), −0.02-−0.15 (m, 2H); 19F NMR (282 MHz, DMSO-d₆) δ −129.12 (q,J=7.7 Hz); MS (ES+) 552.5 (M+1), 554.5 (M+2); Optical rotation:[α]_(D)=(+) 76.66 [0.06, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(70c) Step-1 Preparation of (2R,4R)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(70a)

Compound 70a was prepared from(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(36a) (22 g, 90 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (34.2 g, 88 mmol) and ethyl 2-ethoxyquinoline-1(2H)-carboxylate(24.2 g, 98 mmol) using the reaction and workup conditions as reportedin step 10 of Scheme 1 to afford after purification by flash columnchromatography (silica gel, eluting with 0-100% 9:1 ethylacetate/methanol in hexanes) (2R,4R)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(70a) (38.8 g, 70%) as colorless foam. ¹H NMR data showed product asrotamers; ¹H NMR (300 MHz, DMSO-d₆) δ 9.52 (s, 1H), 8.54-8.45 (m, 2H),7.89 (d, J=7.2 Hz, 1H), 7.36-7.27 (m, 2H), 7.20 (d, J=10.3 Hz, 2H), 5.47(s, 1H), 4.39-4.21 (m, 1H), 4.01-3.89 (m, 1H), 3.63-3.50 (m, 1H),3.27-3.12 (m, 3H), 2.64-2.53 (m, 4H), 1.94-1.83 (m, 1H), 1.47-1.06 (m,19H), 1.00-0.79 (m, 1H), 0.73-0.55 (m, 1H), 0.42-0.26 (m, 2H),−0.02-−0.16 (m, 2H); MS (ES+) 617.7 (M+1), MS(ES−) 615.6 (M−1), 651.6(M+Cl); Optical Rotation [α]_(D)=(−) 48.2 [0.17, MeOH].

Step-2: Preparation of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(70b)

Reaction of (2R,4R)-tert-butyl2-(5-((−)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(70a) (30 g, 48.7 mmol) in methanol (300 mL) with 3N HCl in methanol(130 mL, 400 mmol) gave after workup and purification as reported instep 6 of Scheme 4(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(70b) (25 g, 100% yield) as a hydrochloride salt which was pure enoughto be used as such in next step.

Step-3:(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(70c)

Reaction of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(70b) (25.9 g, 48.7 mmol) in tetrahydrofuran/water (600/40 mL) withphenyl 5-chloropyridin-2-ylcarbamate (13b) (10.8 g, 43.8 mmol) usingsodium bicarbonate (33 g, 400 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel, eluting with using 0-100% CMA-80 inChloroform) to afford(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(70c) (14 g, 47%) free base as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 9.45 (s, 1H), 9.15 (s, 1H), 8.48-8.40 (m, 2H), 8.30 (dd, J=2.6, 0.8Hz, 1H), 7.95-7.85 (m, 2H), 7.81 (dd, J=9.0, 2.6 Hz, 1H), 7.38-7.30 (m,2H), 7.19-7.10 (m, 2H), 4.57 (dd, J=9.2, 4.0 Hz, 1H), 4.03 (m, 1H), 3.72(qd, J=10.8, 4.3 Hz, 2H), 3.20 (s, 3H), 2.40-2.24 (m, 2H), 2.19 (t,J=8.0 Hz, 2H), 2.09 (m, 1H), 1.03 (m, 2H), 0.62 (m, 1H), 0.40-0.28 (m,2H), −0.07 (s, 2H). The free base (8.5 g, 15 mmol) was converted tohydrochloride salt using conc. HCl (2.87 mL) in ethanol (30 mL) toafford compound 70c (9.3 g) hydrochloride as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.76-9.69 (m, 1H), 9.63 (s, 4H), 9.23 (s, 1H), 8.85 (s,2H), 8.31 (dd, J=2.6, 0.8 Hz, 1H), 8.01-7.92 (m, 1H), 7.85 (qd, J=9.0,1.7 Hz, 2H), 7.72 (brs, 2H), 7.38 (dd, J=10.4, 8.8 Hz, 1H), 7.23 (s,1H), 4.61 (dd, J=9.2, 4.2 Hz, 1H), 4.05 (d, J=4.8 Hz, 1H), 3.78 (dd,J=10.9, 5.2 Hz, 1H), 3.73-3.62 (m, 1H), 3.21 (s, 3H), 2.41 (m, 2H), 2.06(m, 1H), 1.14 (m, 2H), 0.68 (m, 1H), 0.43-0.29 (m, 2H), 0.03 (m, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ −125.00; MS (ES+) 567.3 (M+1), 569.3 (M+2),MS (ES−) 601.2 (M+Cl); Optical Rotation [α]_(D)=(+) 96.4 [0.5, MeOH];Analysis calculated for C₂₉H₃₂ClFN₆O₃.2.25HCl.2.0H₂O: C, 50.84; H, 5.63;Cl, 16.82; N, 12.27. Found: C, 50.98; H, 5.67; Cl, 16.72; N, 12.12.

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(71a)

Reaction of(2R,4R)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(70b) (0.5 g, 0.97 mmol) in tetrahydrofuran/water (20/2 mL) with4-chlorophenyl isocyanate (1n) (0.13 g, 0.87 mmol) using sodiumbicarbonate (0.33 g, 0.4 mmol) as base according to procedure reportedin step 9 of Scheme 1 gave after purification by flash columnchromatography (silica gel, eluting with using 0-30% CMA-80 inChloroform)(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(4-chlorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(71a) (0.1 g, 18% yield) as a colorless foam; ¹H NMR (300 MHz, DMSO-d₆)δ 9.60 (s, 1H), 8.62-8.50 (m, 3H), 7.94 (dd, J=7.4, 2.4 Hz, 1H),7.61-7.49 (m, 2H), 7.38-7.22 (m, 5H), 7.16-7.06 (m, 1H), 4.55 (dd,J=9.2, 4.1 Hz, 1H), 4.07 (d, J=5.3 Hz, 1H), 3.79-3.69 (m, 1H), 3.61 (dd,J=10.3, 3.4 Hz, 1H), 3.22 (s, 3H), 2.48-2.23 (m, 3H), 2.14-2.02 (m, 1H),1.08 (m, 2H), 0.67 (m, 1H), 0.44-0.30 (m, 2H), −0.03 (m, 2H); HPLC:6.602 (98%); MS (ES+) 565.4 (M+), 567.4 (M+2), MS (ES−) 564.5 (M+),600.5 (M+Cl); Analysis calculated for C₃₀H₃₃ClFN₅O₃.3H₂O: C, 58.11; H,6.34; N, 11.29. Found: C, 58.01; H, 5.98; N, 10.96.

The free base of compound 71a was converted to hydrochloride salt usingconc. HCl in ethanol to afford compound 71a hydrochloride salt as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.71 (s, 1H), 9.55 (s, 3H),8.81 (d, J=5.1 Hz, 2H), 8.59 (s, 1H), 7.98 (dd, J=7.3, 2.5 Hz, 1H), 7.64(d, J=5.7 Hz, 1H), 7.60-7.50 (m, 2H), 7.38 (dd, J=10.5, 8.8 Hz, 1H),7.32-7.25 (m, 2H), 7.21 (s, 1H), 4.57 (dd, J=9.2, 4.2 Hz, 1H), 4.07 (d,J=4.7 Hz, 1H), 3.81-3.69 (m, 1H), 3.62 (dd, J=10.3, 3.4 Hz, 1H), 3.23(s, 3H), 2.45-2.35 (m, 3H), 2.14-2.00 (m, 1H), 1.30-0.98 (m, 2H), 0.69(m, 1H), 0.38 (m, 2H), 0.07-0.01 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−125.33; MS (ES+) 565.4 (M+1), 567.4 (M+2), 588.4, 590.4 (M+Na), MS(ES−) 564.5 (M−1), 600.4 (M+Cl); Optical Rotation [α]_(D)=(+) 67.9[0.28, MeOH]; Analysis calculated for C₃₀H₃₃ClFN₅O₃.2HCl.2.75H₂O: C,52.33; H, 5.93; Cl, 15.45; N, 10.17. Found: C, 52.68; H, 5.94; Cl,15.30; N, 9.89.

Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide(72c) Step-1: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(72a)

Reaction of(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(14b) (0.16 g, 0.69 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (0.27 g, 0.69 mmol) in tetrahydrofuran (5 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.17 g, 0.7 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(72a) (0.17 g, 40%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.80(s, 1H), 8.48 (dt, J=6.1, 2.3 Hz, 2H), 7.98 (d, J=7.4 Hz, 1H), 7.35-7.26(m, 2H), 7.20 (d, J=11.7 Hz, 2H), 5.49 (d, J=12.6 Hz, 1H), 5.36-5.17 (m,1H), 4.35-4.15 (m, 2H), 3.57-3.42 (m, 1H), 3.29-3.16 (m, 1H), 2.44-2.30(m, 1H), 1.89-1.73 (m, 1H), 1.46-1.01 (m, 19H), 0.97-0.79 (m, 1H),0.70-0.50 (m, 1H), 0.43-0.27 (m, 2H), −0.03-−0.15 (m, 2H); MS (ES+)603.5 (M+1), 625.5 (M+Na), MS (ES−) 601.5 (M−1).

Step-2: Preparation of(2R,4R)-N-(5-((S)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(72b)

Reaction of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(72a) (0.17 g, 0.27 mmol) in methanol (10 mL) using 3N HCl in methanol(1 mL) followed by workup and purification as reported in step 6 ofScheme 4 gave (2R,4R)-N-(5-((S)-1-amino-3-cyclopropyl-1(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(72b) as a yellow oil, which was used as such in next step withoutfurther purification.

Step-3: Preparation of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide(72c)

Reaction of(2R,4R)-N-(5-((S)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-hydroxypyrrolidine-2-carboxamide(72b) obtained in above step 2 in tetrahydrofuran/water (8 mL/1 mL) withphenyl 5-chloropyridin-2-ylcarbamate (13b) (0.06 g, 0.25 mmol) usingsodium bicarbonate (0.23 g, 2.7 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel 24 g, eluting with CMA-80 in chloroform0-30%) (0.1 g, 74% yield) free base as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.67 (s, 1H), 9.17 (s, 1H), 8.47-8.38 (m, 2H), 8.32 (s, 1H),8.29 (dd, J=2.6, 0.8 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.88 (dd, J=9.1,0.8 Hz, 1H), 7.79 (dd, J=9.0, 2.6 Hz, 1H), 7.39-7.30 (m, 2H), 7.13 (d,J=7.9 Hz, 1H), 5.31 (s, 1H), 4.54 (dd, J=9.0, 4.8 Hz, 1H), 4.30 (s, 1H),3.72 (dd, J=10.4, 5.3 Hz, 1H), 3.50 (q, J=5.0, 4.1 Hz, 1H), 2.45-2.09(m, 5H), 1.96-1.80 (m, 1H), 1.10-0.90 (m, 2H), 0.70-0.53 (m, 1H),0.41-0.22 (m, 2H), −0.02-−0.16 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−125.05; MS (ES+) 553.5 (M+1), 555.4 (M+2), 575.4, 577.4 (M+Na), MS(ES−) 587.4 (M+Cl). The free base was converted into HCl salt using concHCl in ethanol (5 mL) to afford compound 72c HCl salt as a white solid;1H NMR (300 MHz, DMSO-d₆) δ 9.93 (s, 1H), 9.70 (s, 3H), 9.27 (s, 1H),8.95-8.86 (m, 2H), 8.30 (dd, J=2.5, 0.9 Hz, 1H), 8.10 (dd, J=7.2, 2.5Hz, 1H), 7.90-7.76 (m, 4H), 7.39 (dd, J=10.5, 8.8 Hz, 1H), 7.23 (dd,J=7.3, 4.5 Hz, 1H), 4.57 (dd, J=8.9, 5.1 Hz, 1H), 4.33 (t, J=5.1 Hz,1H), 3.75 (dd, J=10.4, 5.4 Hz, 1H), 3.56-3.45 (m, 1H), 2.60-2.53 (m,2H), 2.47-2.33 (m, 2H), 1.87 (m, 1H), 1.30-0.96 (m, 2H), 0.69 (m, 1H),0.37 (m, 2H), 0.08-0.01 (m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −125.05;MS (ES+) 553.5 (M+1), 555.4 (M+2), 575.4, 577.4 (M+Na), MS (ES−) 587.4(M+Cl); Optical rotation [α]_(D)=(+) 82.96 [0.27, MeOH].

Preparation of(2R,4R)-N2-(5-((+)-1-acetamido-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(73a)

Reaction of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(70c) (113 mg, 0.2 mmol) at 0° C. in dichloromethane (3 mL) usingpyridine (126 mg, 1.6 mmol) and acetic anhydride (81 mg, 0.8 mmol) asreported in Scheme 55 gave(2R,4R)-N2-(5-((+)-1-acetamido-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(73a) (91 mg, 75%) free base as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 9.49 (s, 1H), 9.17 (s, 1H), 8.45 (d, J=5.8 Hz, 2H), 8.30 (dd, J=2.7,0.8 Hz, 2H), 7.94-7.76 (m, 3H), 7.30-7.23 (m, 2H), 7.22-7.05 (m, 2H),4.58 (dd, J=9.2, 4.0 Hz, 1H), 4.04 (d, J=5.4 Hz, 1H), 3.73 (td, J=11.3,6.2 Hz, 3H), 3.21 (s, 3H), 2.43-2.23 (m, 2H), 2.10 (m, 1H), 1.90 (s,3H), 0.91 (m, 2H), 0.62 (m, 1H), 0.38-0.33 (m, 2H), −0.13-−0.13 (m, 2H).¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.00; MS (ES+) 609.4 (M+1), 631.4(M+Na), MS (ES−) 607.4 (M−), 643.4 (M+Cl); The free base was convertedto HCl salt to afford compound 73a HCl salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.60 (s, 1H), 9.22 (s, 1H), 8.75 (d, J=6.2 Hz, 2H),8.69 (s, 1H), 8.30 (dd, J=2.6, 0.9 Hz, 1H), 7.97 (d, J=6.9 Hz, 1H),7.94-7.88 (m, 3H), 7.86 (d, J=0.9 Hz, 1H), 7.81 (dd, J=9.0, 2.6 Hz, 1H),7.31-7.18 (m, 2H), 4.59 (dd, J=9.2, 4.1 Hz, 1H), 4.10-4.00 (m, 1H), 3.73(qd, J=10.8, 4.3 Hz, 2H), 3.22 (s, 3H), 2.78-2.53 (m, 2H), 2.47-2.32 (m,1H), 2.15-2.00 (m, 1H), 1.94 (s, 3H), 1.09-0.93 (m, 2H), 0.74-0.57 (m,1H), 0.34 (d, J=2.0 Hz, 1H), 0.04-−0.14 (m, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −127.10; MS (ES+) 609.3 (M+1) 631.3 (M+Na); MS (ES−) 643.3(M+Cl); HPLC purity (87.9048%); Optical rotation [α]_(D)=(+) 105.84[0.565, MeOH]; Analysis calculated for C₃₁H₃₄ClFN₆O₄.1.75HCl.2H₂O: C,52.52; H, 5.65; Cl, 13.75; N, 11.85. Found: C, 52.28; H, 5.81; Cl,13.92; N, 11.67.

Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(74a)

Reaction of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(70a) (57 mg, 0.1 mmol) at 0° C. in dichloromethane (3 mL) usingpyridine (78 mg, 1 mmol) and methanesulfonic anhydride (68 mg, 0.4 mmol)according to the procedure as reported in Scheme 55 gave afterpurification by flash column chromatography (silica gel 12 g, elutingwith MeOH in Chloroform 0 to 10%)(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(74a) (25 mg, 40% yield) free base as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.58 (s, 1H), 9.18 (s, 1H), 8.42-8.25 (m, 2H), 8.01-7.75 (m,5H), 7.33-7.17 (m, 1H), 7.08 (s, 1H), 4.68-4.53 (m, 1H), 4.04 (d, J=5.9Hz, 1H), 3.89-3.61 (m, 2H), 3.19 (s, 3H), 2.61-2.31 (m, 3H), 2.28 (s,3H), 2.10 (m, 1H), 1.14-0.96 (m, 1H), 0.86 (m, 1H), 0.65-0.49 (m, 1H),0.43-0.22 (m, 2H), −0.01-−0.23 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−126.45; MS (ES+) 645.3 (M+1), 667.3 (M+Na), (ES−) 643.4 (M−1). The freebase was converted to HCl salt to furnish compound 74a hydrochloride asa white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.63 (s, 1H), 9.19 (s, 1H),8.81 (d, J=6.2 Hz, 2H), 8.30 (d, J=2.6, Hz, 1H), 8.14 (s, 1H), 7.97 (d,J=7.9 Hz, 1H), 7.88 (q, J=4.1, 2.8 Hz, 3H), 7.82 (dd, J=9.0, 2.6 Hz,1H), 7.29 (dd, J=10.3, 8.8 Hz, 1H), 7.11 (m, 1H), 4.61 (dd, J=9.2, 4.1Hz, 1H), 4.05 (t, J=4.4 Hz, 1H), 3.78 (m, 1H), 3.21 (s, 3H), 2.78-2.59(m, 1H), 2.42 (s, 3H), 2.40-2.34 (m, 1H), 2.17-2.02 (m, 1H), 1.37-0.95(m, 2H), 0.91-0.70 (m, 2H), 0.60 (m, 1H), 0.33 (m, 2H), −0.03-−0.13 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −125.93; MS (ES+) 645.3 (M+1), 667.3(M+Na), MS (ES−) 679.4 (M+Cl); Optical rotation [α]_(D)=(+) 82.96 [0.27,MeOH].

Preparation of(2R,4R)-N2-(3-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(75e) Step-1 Preparation of(R)-N-((−)-1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(75b)

Compound (75b) was prepared from(−)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide(39d) (4.3 g, 15.5 mmol) and(3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide (34 mL, 34 mmol,1M solution in THF) using procedure as reported in step 4 of scheme 31to afford(R)-N-((−)-1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(75b) (1.9 g, 33%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.51-8.42 (m, 2H), 7.37-7.29 (m, 2H), 6.94 (t, J=7.8 Hz, 1H), 6.52 (t,J=2.0 Hz, 1H), 6.47 (dd, J=7.8, 1.4 Hz, 1H), 6.42-6.34 (m, 1H), 5.15 (s,1H), 5.05 (s, 2H), 1.14 (s, 10H), 1.05-0.75 (m, 1H), 2.73-2.33 (m, 2H),0.75-0.53 (m, 1H), 0.43-0.27 (m, 2H), −0.00-−0.21 (m, 2H); Opticalrotation [α]_(D)=(−) 90.34 [0.23, MeOH].

Step-2: Preparation of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(75c)

Compound 75c was prepared from(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(36a) (245 mg, 1 mmol),(R)-N-((−)-1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(75b) (0.37 g, 1 mmol) and ethyl 2-ethoxyquinoline-1(2H)-carboxylate(250 mg, 1 mmol) using the reaction and workup conditions as reported instep 10 of Scheme 1 to afford (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(75c) 0.44 g, 73% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.76 (2s, 1H, rotamers), 8.54-8.43 (m, 2H), 7.65-7.38 (m, 2H), 7.37-7.18(m, 3H), 7.06 (2 dd, 1H, rotamers), 5.39 (2s, 1H, rotamers), 4.19 (m,1H), 3.97 (m, 1H), 3.64 (dd, J=10.6, 6.1 Hz, 1H), 3.20 (2s, 3H,rotamers), 2.44 (m, 3H), 1.94-1.76 (m, 1H), 1.23 (2s, 9H, rotamers),1.19-1.04 (m, 10H), 0.99-0.79 (m, 2H), 0.73-0.54 (m, 1H), 0.42-0.28 (m,2H), 2.75-2.37 (m, 3H), −0.03-−0.18 (m, 2H).

Step-3: Preparation of(2R,4R)-N-(3-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-4-methoxypyrrolidine-2-carboxamide(75d)

Reaction of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(75c) (0.44 g, 0.73 mmol) in methanol (10 mL) with 3N HCl in MeOH (1 mL)gave after workup and purification as reported in step 6 of Scheme 4(2R,4R)-N-(3-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-4-methoxypyrrolidine-2-carboxamide(75d) as a hydrochloride salt which was used as such for next step.

Step-4:(2R,4R)-N2-(3-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(75e)

Reaction of(2R,4R)-N-(3-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-4-methoxypyrrolidine-2-carboxamide(75d) (0.37 g, 0.73 mmol) in tetrahydrofuran/water (25 mL/1 mL) withphenyl 5-chloropyridin-2-ylcarbamate (13b) (0.173 g, 0.7 mmol) usingsodium bicarbonate (0.47 g, 5.6 mmol) as base according to procedurereported in step 3 of Scheme 13 gave after purification by flash columnchromatography (silica gel 24 g, CMA80 in Chloroform 0 to 30%)(2R,4R)-N2-(3-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(75e) (0.31 g, 80%) free base as a white solid, which was converted tohydrochloride salt to furnish compound 75c HCl salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 9.99 (s, 1H), 9.41 (s, 3H), 9.18 (s, 1H), 8.80(s, 2H), 8.30 (d, J=2.6 Hz, 1H), 7.92-7.75 (m, 2H), 7.71-7.54 (m, 4H),7.39 (t, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 4.50 (m, 1H), 4.04 (t,J=5.2 Hz, 1H), 3.85 (dd, J=10.7, 5.8 Hz, 1H), 3.58 (dd, J=10.6, 4.4 Hz,1H), 3.20 (s, 3H), 2.44 (m, 3H), 1.97 (m, 1H), 1.12 (m, 2H), 0.70 (m,1H), 0.38 (m, 2H), 0.00 (m, 2H); MS (ES+) 562.4 (M+Na), 549.6 (M+),(ES−) 583.5, (M+Cl); Optical rotation [α]_(D)=(+) 95.32 [0.235, MeOH];Analysis calculated for C₂₉H₃₃ClN₆O₃.2.5HCl.3.25H₂O: C, 49.85; H, 6.06;Cl, 17.76; N, 12.03. Found: C, 49.73; H, 5.89; Cl, 17.83; N, 11.88.

Preparation of(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(2-(4-chlorophenyl)acetyl)-4-methoxypyrrolidine-2-carboxamide(76e) Step-1 Preparation of (2R,4R)-4-methoxypyrrolidine-2-carboxylicacid (76a)

Compound 76a was prepared by hydrolysis of Boc protecting group on(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(36a) (0.49 g, 2 mmol) in methanol (3 mL) with 3N HCl in MeOH (3 mL) asreported in step 6 of Scheme 4. This gave after workup(2R,4R)-4-methoxypyrrolidine-2-carboxylic acid (76a) hydrochloride saltas an off-white solid, which was used without further purification.

Step-2: Preparation of(2R,4R)-1-(2-(4-chlorophenyl)acetyl)-4-methoxypyrrolidine-2-carboxylicacid (76c)

To a solution of (2R,4R)-4-methoxypyrrolidine-2-carboxylic acid (76a) (2mmol, obtained in step 1) in dichloromethane (20 mL) was added Pyridine(1 g, 12.5 mmol), 4-chloro phenyl acetyl chloride (76b) (0.38 g, 2 mmol)and stirred at room temperature overnight. The reaction was diluted withdichloromethane (20 mL), saturated aqueous NaHCO₃ (40 mL) solution andstirred for few mins. The aqueous layer was separated, acidified with 1NHCl (5 mL), and extracted with ethyl acetate (2×30 mL). The ethylacetate layers were combined washed with brine, dried (MgSO₄), filteredand concentrated to afford(2R,4R)-1-(2-(4-chlorophenyl)acetyl)-4-methoxypyrrolidine-2-carboxylicacid (76c) (0.25 g, 42% yield) as a gummy solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.38 (s, 1H), 7.43-7.17 (m, 4H), 4.34 (m, 1H), 4.05-3.95 (m,1H), 3.87-3.77 (m, 2H), 3.68 (s, 2H), 3.52-3.42 (m, 2H), 3.17 (2s, 3H);MS (ES+) 320.2 (M+Na); (ES−) 296.2 (M−1), 332.2 (M+Cl).

Step-3: Preparation of(2R,4R)-1-(2-(4-chlorophenyl)acetyl)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(76d)

Compound 76d was prepared from(2R,4R)-1-(2-(4-chlorophenyl)acetyl)-4-methoxypyrrolidine-2-carboxylicacid (76c) (80 mg, 0.27 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (0.1 g, 0.27 mmol) and ethyl 2-ethoxyquinoline-1(2H)-carboxylate(100 mg, 0.27 mmol) using the reaction and workup conditions as reportedin step 10 of Scheme 1 to afford after purification by flash columnchromatography (silica gel 24 g, CMA80 in Chloroform 0 to 30%)(2R,4R)-1-(2-(4-chlorophenyl)acetyl)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(76d) (0.135 g, 75%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.42(s, 1H), 8.55-8.44 (m, 2H), 7.89 (d, J=7.0 Hz, 1H), 7.41-7.05 (m, 8H),5.54 (s, 1H), 4.57-4.42 (m, 1H), 4.07-3.77 (m, 3H), 3.78-3.68 (m, 2H),3.65-3.55 (m, 1H), 3.18 (s, 3H), 2.61 (m, 3H), 2.40-2.22 (m, 2H),1.18-1.08 (m, 10H), 1.01-0.81 (m, 1H), 0.70-0.54 (m, 1H), 0.42-0.29 (m,2H), −0.02-−0.14 (m, 2H); MS (ES+) 669.5 (M+), 691.5 (M+Na), MS (ES−)667.5 (M−1).

Step-4: Preparation of(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(2-(4-chlorophenyl)acetyl)-4-methoxypyrrolidine-2-carboxamide(76e)

Reaction of(2R,4R)-1-(2-(4-chlorophenyl)acetyl)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(76d) (0.13 g, 0.19 mmol) in ethanol (10 mL) with conc HCl (0.2 mL) gaveafter workup and purification as reported in step 6 of Scheme 4(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(2-(4-chlorophenyl)acetyl)-4-methoxypyrrolidine-2-carboxamide(76e) (0.09 g, 86% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆, at350 Kelvin) δ 9.07 (s, 1H), 8.49-8.40 (m, 2H), 7.92 (s, 1H), 7.40-7.22(m, 6H), 7.20-7.05 (m, 3H), 4.58 (m, 1H), 4.04 (m, 1H), 3.90-3.46 (m,4H), 3.23 (s, 3H), 2.42-2.10 (m, 5H), 1.21-1.01 (m, 2H), 0.77-0.55 (m,1H), 0.43-0.24 (m, 2H), 0.01-−0.16 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.37; MS (ES+) 565.4, 567.3 MS (ES−) 563.4, 599.3; Optical rotation[α]_(D)=(+) 60.3 [0.335, MeOH]; Analysis calculated forC₃₁H₃₄ClFN₄O₃.0.25H₂O: C; 65.37, H; 6.11, N; 9.84. Found: C; 65.18, H;6.09, N; 9.63.

Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(ethylamino)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(77a)

Reductive amination of(2R,4R)-N2-(5-((S)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(70c) (0.1 g, 0.17 mmol) in MeOH (3 mL) using acetaldehyde (0.1 mL, 1.7mmol) and sodium borohydride (0.02 g, 0.53 mmol) according to theprocedure reported in Scheme 41 gave after workup and purification(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(ethylamino)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(77a) (55 mg, 52.4% yield) free base as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.46 (s, 1H), 9.16 (s, 1H), 8.44 (d, J=6.0 Hz, 2H), 8.30 (dd,J=2.6, 0.8 Hz, 1H), 7.95-7.74 (m, 3H), 7.31 (d, J=6.0 Hz, 2H), 7.17-7.05(m, 2H), 4.58 (d, J=5.6 Hz, 1H), 4.09-3.97 (m, 1H), 3.81-3.63 (m, 2H),3.20 (s, 3H), 2.44-2.31 (m, 4H), 2.23 (t, J=8.1 Hz, 1H), 2.16-2.03 (m,2H), 0.99 (t, J=7.0 Hz, 3H), 0.94-0.77 (m, 2H), 0.69-0.53 (m, 1H),0.39-0.27 (m, 2H), −0.09-−0.19 (m, 2H); The free base was converted toHCl salt using conc HCl in ethanol to afford compound 77a hydrochlorideas a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.99 (s, 1H), 9.74 (s,1H), 9.24 (s, 1H), 8.81 (s, 3H), 8.31 (d, J=1.8 Hz, 1H), 8.00 (d, J=6.7Hz, 1H), 7.92-7.79 (m, 2H), 7.79-7.63 (m, 1H), 7.49-7.33 (m, 1H),7.33-7.19 (m, 1H), 4.61 (dd, J=8.8, 4.0 Hz, 1H), 4.13-3.98 (m, 1H),3.87-3.61 (m, 2H), 3.21 (s, 3H), 2.96-2.73 (m, 1H), 2.70-2.54 (m, 4H),2.46-2.30 (m, 2H), 2.17-1.97 (m, 1H), 1.22 (t, J=6.6 Hz, 3H), 1.10-0.77(m, 2H), 0.73-0.54 (m, 1H), 0.46-0.26 (m, 2H), 0.02-−0.15 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ −124.33; MS (ES+) 595.3 (M+1), 617.3 (M+Na),(ES−) 593.3 (M−1), 529.3 (M+Cl); Optical rotation [α]_(D)=(+) 77.78[0.27, MeOH]; Analysis calculated for C₃₁H₃₆ClFN₆O₃.2.25HCl.2.5H₂O: C,51.56; H, 6.04; Cl, 15.95; N, 11.64. Found: C, 51.48; H, 5.89; Cl,16.23; N, 11.43.

Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(ethylamino)-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(78a)

Reductive amination of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(46k) (0.68 g, 1.169 mmol) in THF/MeOH (25 mL, 4:1) using acetaldehyde(6.8 mL), acetic acid (1 mL) and sodium borohydride (0.619 g, 16.366mmol) according to the procedure reported in Scheme 41 gave after workupand purification(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(ethylamino)-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(78a) (120 mg, 16.79%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.45 (s, 1H), 9.15 (s, 1H), 8.42-8.09 (m, 2H), 7.98-7.64 (m, 3H),7.34-6.98 (m, 4H), 4.68-4.47 (m, 1H), 4.13-3.90 (m, 1H), 3.84-3.60 (m,2H), 3.21 (s, 3H), 2.49 (s, 2H), 2.41 (s, 3H), 2.27-2.17 (m, 2H),2.14-2.01 (m, 3H), 0.99 (t, J=6.5 Hz, 3H), 0.93-0.78 (m, 2H), 0.70-0.50(m, 1H), 0.42-0.18 (m, 2H), −0.04-−0.24 (m, 2H); MS (ES+) 609.5, 610.5,611.5 (M+1); Optical rotation [α]_(D)=(+) 74.87 [0.195, MeOH].

Preparation of(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((+)-3-cyclopropyl-1-(methylamino)-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(79a)

Reductive amination of(2R,4R)-N2-(5-((+)-1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chloropyridin-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(46k) (0.3 g, 0.516 mmol) in THF/MeOH (20 mL, 4:1) usingparaformaldehyde (0.465 g, 5.16 mmol), acetic acid (0.5 mL) and sodiumborohydride (0.195 g, 0.516 mmol) according to the procedure reported inScheme 41 gave after workup and purification(2R,4R)-N1-(5-chloropyridin-2-yl)-N2-(5-((S)-3-cyclopropyl-1-(methylamino)-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(79a) (80 mg, 25.97%) as a white solid; ¹H NMR (300 MHz, DMSO-d6) δ9.45(s, 1H), 9.15 (s, 1H), 8.37-8.20 (m, 2H), 7.96-7.74 (m, 3H), 7.30-6.97(m, 4H), 4.58 (dd, J=9.1, 3.9 Hz, 1H), 4.07-3.98 (m, 1H), 3.82-3.60 (m,2H), 3.20 (s, 3H), 2.43-2.38 (m, 2H), 2.40 (s, 3H), 2.20 (t, J=8.1 Hz,2H), 2.13-2.06 (m, 1H), 1.92 (s, 3H), 0.93-0.75 (m, 2H), 0.68-0.52 (m,1H), 0.39-0.29 (m, 2H), −0.05-−0.21 (m, 2H); MS (ES−) 593.5, 595.5(M−1); Optical rotation [α]_(D)=(+) 29.19 [0.185, MeOH].

Preparation of(1R,3R,5R)-N3-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N2-(5-chloropyridin-2-yl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide(80d) Step-1: Preparation of (1R,3R,5R)-tert-butyl3-(5-(3-cyclopropyl-1-((−)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(80b)

Reaction of(1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (80a) (98 mg, 0.431 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (168 mg, 0.431 mmol) in tetrahydrofuran (15 mL) using ethyl2-ethoxyquinoline-1(2H)-carboxylate (107 mg, 0.431 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 gave(1R,3R,5R)-tert-butyl3-(5-(3-cyclopropyl-1-((−)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(80b) (132 mg, 51% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d6) δ9.80 (s, 1H), 8.49 (d, J=6.0 Hz, 2H), 7.99-7.82 (m, 1H), 7.32 (d, J=5.8Hz, 2H), 7.24-7.03 (m, 2H), 5.51 (s, 1H), 4.80-4.61 (m, 1H), 1.97-1.79(m, 1H), 1.55-1.47 (m, 1H), 1.44-1.37 (m, 3H), 1.26 (s, 9H), 1.13 (s,9H), 1.03-0.84 (m, 4H), 0.70-0.56 (m, 2H), 0.41-0.29 (m, 2H),−0.02-−0.12 (m, 2H); MS (ES⁺) 599.7 (M+1), 621.7 (M+Na); Opticalrotation [α]_(D)=(−) 30.0 [0.08, MeOH].

Step-2: Preparation of(1R,3R,5R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(80c)

Reaction of (1R,3R,5R)-tert-butyl3-(5-(3-cyclopropyl-1-((−)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(80b) (132 mg, 0.220 mmol) in ethanol (10 mL) using conc. HCl inmethanol (0.033 mL, 1.102 mmol) followed by workup and purification asreported in step 6 of Scheme 4 gave(1R,3R,5R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(80c) (111 mg, 0.224 mmol, 100% yield) hydrochloride salt as a yellowsolid, which was used in the next step without further purification; ¹HNMR (300 MHz, DMSO-d6) δ 10.63 (s, 2H), 9.74 (s, 2H), 9.02-8.76 (m, 3H),7.81-7.68 (m, 3H), 7.48-7.30 (m, 2H), 4.78 (s, 1H), 3.37 (s, 2H),2.75-2.55 (m, 2H), 2.18 (d, J=10.8 Hz, 1H), 1.84-1.72 (m, 1H), 1.22 (d,J=7.2 Hz, 1H), 0.87 (d, J=7.3 Hz, 1H), 0.73 (d, J=20.9 Hz, 2H), 0.39 (d,J=7.8 Hz, 2H), 0.04 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −122.43; MS (ES⁺)395.5 (M+1); Optical rotation [α]_(D)=(+) 6.67 [0.09, MeOH].

Step-3: Preparation of(1R,3R,5R)-N3-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N2-(5-chloropyridin-2-yl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide(80d)

Reaction of(1R,3R,5R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(80c) obtained in above step 2 (49.3 mg, 0.198 mmol) in tetrahydrofuran(10 mL) with phenyl 5-chloropyridin-2-ylcarbamate (13b) (49.3 mg, 0.198mmol) using potassium carbonate (76 mg, 0.551 mmol) as base according toprocedure reported in step 3 of Scheme 13 gave after purification byflash column chromatography (silica gel 24 g, eluting with CMA-80 inchloroform 0-40%)(1R,3R,5R)-N3-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N2-(5-chloropyridin-2-yl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide(80d) (52 mg, 0.095 mmol, 47.8% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.77 (s, 1H), 9.23 (s, 1H), 8.52-8.34 (m, 2H), 8.29 (s,1H), 7.98-7.72 (m, 3H), 7.44-7.21 (m, 2H), 7.13 (d, J=7.3 Hz, 2H), 4.93(d, J=11.2 Hz, 1H), 3.83 (s, 1H), 2.68-2.55 (m, 1H), 2.45-2.30 (m, 1H),2.27-2.07 (m, 2H), 1.95 (d, J=13.3 Hz, 1H), 1.76-1.55 (m, 1H), 1.24 (s,1H), 1.16-0.95 (m, 2H), 0.91-0.76 (m, 1H), 0.75-0.53 (m, 2H), 0.43-0.22(m, 2H), −0.04-−0.24 (m, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −122.43; ¹⁹F NMR(282 MHz, DMSO) δ −127.55; MS (ES⁺) 549.6 (M+1); Optical rotation[α]_(D)=(+) 68.46 [0.26, MeOH].

Preparation of(2R,4R)-N2-(5-((−)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chlorothiophen-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(81h) Step-1 Preparation of (2R,4R)-1-tert-butyl 2-methyl4-methoxypyrrolidine-1,2-dicarboxylate (81a)

To a solution of(2R,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid(36a) (2.45 g, 9.99 mmol) in DMF (30 mL) was added K₂CO₃ (1.381 g, 9.99mmol), CH₃I (1.249 mL, 19.98 mmol), stirred at room temperature for 48h, diluted with water (200 mL) and EtOAc (100 mL). Aqueous layer wasextracted with EtOAc (100 mL) and combined organic layers were washedwith water (100 mL), brine, dried (MgSO4), filtered, concentrated invacuum to afford (2R,4R)-1-tert-butyl 2-methyl4-methoxypyrrolidine-1,2-dicarboxylate (81a) (2.5 g, 9.64 mmol, 97%) aslight orange colored thick syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 4.34-4.17(m, 1H), 3.99-3.84 (m, 1H), 3.67-3.57 (m, 3H), 3.56-3.45 (m, 1H),3.29-3.19 (m, 1H), 3.19-3.10 (2s, 3H, rotamers), 2.45-2.23 (m, 1H),2.08-1.94 (m, 1H), 1.45-1.28 (2s, 9H, rotamers).

Step-2: Preparation of (2R,4R)-methyl 4-methoxypyrrolidine-2-carboxylate(81b)

Reaction of (2R,4R)-1-tert-butyl 2-methyl4-methoxypyrrolidine-1,2-dicarboxylate (81a) (2.4 g, 9.26 mmol) inmethanol (40 mL) with 3N HCl in methanol (9.26 mL, 27.8 mmol) gave afterworkup as reported in step 6 of Scheme 4 (2R,4R)-methyl4-methoxypyrrolidine-2-carboxylate (81b) (1.75 g, 8.94 mmol, 97% yield)as an off-white solid; MS (ES+) 160.2 (M+1).

Step-3: Preparation of 5-chlorothiophene-2-carbonyl azide (81d)

To a solution of 5-chlorothiophene-2-carboxylic acid (81c) (0.5 g, 3.08mmol) in acetone (20 mL) cooled to 0° C. was added triethylamine (0.471mL, 3.38 mmol), ethyl chloroformate (0.325 mL, 3.38 mmol) and stirred at0° C. for 1 h. Sodium azide (0.360 g, 5.54 mmol) was added to reactionmixture and continued stirring at 0° C. for 2 h. the reaction mixturewas poured into 50 mL of ice water and extracted with CH₂Cl₂ (2×40). Thecombined organic layers were washed with water (2×30) and brine, dried,filtered and concentrated in vacuum to afford5-chlorothiophene-2-carbonyl azide (81d) (0.35 g, 1.866 mmol, 60.7%yield) as a white semi solid; ¹H NMR (300 MHz, CDCl₃,) δ 7.67 (d, 1H),6.99 (d, 1H).

Step-4: Preparation of (2R,4R)-methyl1-(5-chlorothiophen-2-ylcarbamoyl)-4-methoxypyrrolidine-2-carboxylate(81e)

A solution of 5-chlorothiophene-2-carbonyl azide (81d) (0.35 g, 1.866mmol) in toluene was heated at 100° C. for 2 h, cooled to roomtemperature and added a solution of (2R,4R)-methyl4-methoxypyrrolidine-2-carboxylate hydrochloride (0.365 g, 1.866 mmol)in dichloromethane (15 mL) and pyridine (0.754 mL, 9.33 mmol). Thereaction mixture was stirred at room temperature for 16 h poured intowater (50 mL) and separated aqueous layer was extracted withdichloromethane (2×30 mL). The dichloromethane layers were combinedwashed with brine, dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash chromatography [silica gel 24 g,eluting with MeOH-EtOAc (9:1) in hexane 0 to 100%] to afford(2R,4R)-methyl1-(5-chlorothiophen-2-ylcarbamoyl)-4-methoxypyrrolidine-2-carboxylate(81e) as a light pink foam (0.24 g, 0.753 mmol, 40.4% yield); ¹H NMR(300 MHz, DMSO-d₆) δ 9.78 (s, 1H), 6.77 (d, J=4.1 Hz, 1H), 6.39 (d,J=4.1 Hz, 1H), 4.52 (d, J=8.4 Hz, 1H), 4.01 (s, 1H), 3.61 (s, 4H),3.49-3.38 (m, 1H), 3.17 (s, 3H), 2.35-2.11 (m, 2H); MS (ES+) 341.2(M+Na), MS (ES−) 317.3 (M−1).

Step-5: Preparation of(2R,4R)-1-(5-chlorothiophen-2-ylcarbamoyl)-4-methoxypyrrolidine-2-carboxylicacid (81f)

Compound (81f) was prepared by hydrolysis of (2R,4R)-methyl1-(5-chlorothiophen-2-ylcarbamoyl)-4-methoxypyrrolidine-2-carboxylate(81e) (0.24 g, 0.753 mmol) in THF (5 mL) using LiOH (0.018 g, 0.753mmol) in water (3 mL) at room temperature according to the procedurereported in scheme 54 step 3 to afford after workup(2R,4R)-1-(5-chlorothiophen-2-ylcarbamoyl)-4-methoxypyrrolidine-2-carboxylicacid (81f) (0.205 g, 0.673 mmol, 89% yield) as a purple foam; MS(ES+)305.4 (M+1), 327.4 (M+Na), MS(ES−) 303.3 (M−1).

Step-6: Preparation of(2R,4R)-N1-(5-chlorothiophen-2-yl)-N2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(81g)

Compound 81g was prepared from(2R,4R)-1-(5-chlorothiophen-2-ylcarbamoyl)-4-methoxypyrrolidine-2-carboxylicacid (81f) (0.1 g, 0.328 mmol),(R)-N-((−)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(39e) (0.128 g, 0.328 mmol) and ethyl2-ethoxyquinoline-1(2H)-carboxylate (0.089 g, 0.361 mmol) using thereaction and workup conditions as reported in step 10 of Scheme 1 toafford after purification by flash column chromatography (silica gel 12g, eluting with 0-100% 9:1 ethyl acetate/methanol in hexanes)(2R,4R)-N1-(5-chlorothiophen-2-yl)-N2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(81g) (0.037 g, 0.055 mmol, 16.67% yield) as off white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.88 (s, 1H), 9.51 (s, 1H), 8.56 (d, J=5.5 Hz, 2H),7.88 (d, J=7.4 Hz, 1H), 7.45 (d, J=5.4 Hz, 2H), 7.19 (q, J=10.8, 9.8 Hz,2H), 6.78 (d, J=4.1 Hz, 1H), 6.44 (d, J=4.1 Hz, 1H), 5.62 (s, 1H),4.57-4.46 (m, 1H), 4.15-4.01 (m, 1H), 3.75-3.62 (m, 1H), 3.62-3.48 (m,1H), 3.21 (s, 3H), 2.66-2.53 (m, 3H), 2.16-2.04 (m, 1H), 1.14 (s, 9H),1.01-0.78 (m, 2H), 0.72-0.56 (m, 1H), 0.41-0.28 (m, 2H), −0.04-−0.14 (m,2H); MS (ES+) 676.6 (M+1), 698.6 (M+Na).

Step-7: Preparation of(2R,4R)-N2-(5-((−)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chlorothiophen-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(81h)

Reaction of(2R,4R)-N1-(5-chlorothiophen-2-yl)-N2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-1,2-dicarboxamide(81g) (0.03 g, 0.044 mmol) in methanol (3 mL) with 3N HCl in methanol(0.074 mL, 0.222 mmol) gave after workup and purification as reported instep 6 of Scheme 4(2R,4R)-N2-(5-((−)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-N1-(5-chlorothiophen-2-yl)-4-methoxypyrrolidine-1,2-dicarboxamide(81h) (0.015 g, 0.026 mmol, 59.1% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.86 (s, 1H), 9.46 (s, 1H), 8.44 (d, J=4.9 Hz, 2H), 7.85(d, J=7.3 Hz, 1H), 7.39-7.31 (m, 2H), 7.23-7.10 (m, 2H), 6.78 (dd,J=4.1, 1.3 Hz, 1H), 6.44 (dd, J=4.2, 1.3 Hz, 1H), 4.51 (dd, J=9.2, 3.7Hz, 1H), 4.06 (d, J=5.7 Hz, 1H), 3.69 (dd, J=10.5, 5.4 Hz, 1H), 3.53 (s,1H), 3.20 (s, 3H), 2.25 (m, 6H), 1.17-0.92 (m, 2H), 0.72-0.56 (m, 1H),0.41-0.30 (m, 2H), −0.04-−0.10 (m, 2H); MS 572.6 (M+1); 570.5 (M−1);Optical Rotation [α]_(D)=(−) 27.42 [0.175, MeOH].

Preparation of(2R,4R)-N-(5-(-(+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(1H-indole-6-carbonyl)-4-methoxypyrrolidine-2-carboxamide(82a)

To a solution of(2R,4R)-N-(3-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-4-methoxypyrrolidine-2-carboxamide(75d) (0.2 g, 0.41 mmol) in DMF (3.0 mL) was added DIPEA (0.3 mL); HATU(0.15 g, 0.41 mmol) and 1H-indole-6-carboxylic acid (0.72 g, 0.37 mmol).The reaction mixture was stirred at room temperature overnight, quenchedwith water (40 mL) and extracted with ethyl acetate (2×40 mL). Theorganic layers were combined washed with brine, dried, filtered andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography (silica gel, 12 g, eluting with 0-10%methanol in ethyl acetate) to afford(2R,4R)-N-(5-(-(+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(1H-indole-6-carbonyl)-4-methoxypyrrolidine-2-carboxamide(82a) (0.02 g, 10% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.32 (s, 1H), 9.64 (s, 1H), 8.50-8.36 (m, 2H), 7.96 (s, 1H), 7.71-7.41(m, 3H), 7.41-7.29 (m, 2H), 7.19 (m, 3H), 6.48 (s, 1H), 4.84-4.66 (m,1H), 4.09-3.88 (m, 1H), 3.88-3.68 (m, 1H), 3.68-3.50 (m, 1H), 3.20 (s,3H), 2.37-2.06 (m, 4H), 2.06-1.85 (m, 1H), 1.02 (m, 2H), 0.64 (m, 1H),0.34 (m, 2H), −0.03-−0.14 (m, 2H); MS (ES+) 556.7 (M+1), 578.6 (M+Na),MS (ES−) 554.6 (M−1); Optical rotation [α]_(D)=(+) 54.19 [0.155, MeOH].

Preparation of(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-chloro-1H-indole-6-carbonyl)-4-methoxypyrrolidine-2-carboxamide(83a)

Reaction of(2R,4R)-N-(3-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-4-methoxypyrrolidine-2-carboxamide(75d) (0.2 g, 0.41 mmol) in DMF (3.0 mL) using DIPEA (0.3 mL); HATU(0.15 g, 0.41 mmol) and 3-chloro-1H-indole-6-carboxylic acid (0.72 g,0.37 mmol) according to the procedure as reported in Scheme 82 gave(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-chloro-1H-indole-6-carbonyl)-4-methoxypyrrolidine-2-carboxamide(83a) (0.05 g, 28% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.61 (s, 1H), 9.66 (s, 1H), 8.44 (d, J=5.2 Hz, 2H), 7.97 (d, J=7.6 Hz,1H), 7.68 (d, J=5.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 1H), 7.37 (m, 3H), 7.16(d, J=7.8 Hz, 2H), 4.75 (t, J=6.9 Hz, 1H), 3.99 (m, 2H), 3.76 (m, 1H),3.65-3.49 (m, 1H), 3.19 (s, 3H), 2.32-2.09 (m, 4H), 2.06-1.87 (m, 1H),1.13-0.92 (m, 2H), 0.71-0.56 (m, 1H), 0.42-0.25 (m, 2H), −0.02-−0.13 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −128.16; MS (ES+) 590.7 (M+1), 612.6(M+Na), MS(ES−) 588.6 (M−1); Optical rotation [α]_(D)=(+) 51.43 [0.21,MeOH].

Preparation of(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-amino-4-chlorobenzoyl)-4-methoxypyrrolidine-2-carboxamide(84a)

Reaction of(2R,4R)-N-(3-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-4-methoxypyrrolidine-2-carboxamide(75d) (0.44 g, 0.852 mmol) in DMF (5.0 mL) using DIPEA (0.7 mL, 3.99mmol); EDCI (0.197 g, 1.275 mmol), HOBt (0.195 g, 1.275 mmol) and3-amino-4-chlorobenzoic acid (0.184 g, 1.064 mmol) according to theprocedure as reported in Scheme 82 gave(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-amino-4-chlorobenzoyl)-4-methoxypyrrolidine-2-carboxamide(84a) (0.06 g, 12% yield) as off white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 9.64 (s, 1H), 8.53-8.37 (m, 2H), 7.97 (d, J=7.7 Hz, 1H), 7.42-7.32 (m,2H), 7.25 (d, J=8.2 Hz, 1H), 7.15 (d, J=7.9 Hz, 2H), 6.98 (d, J=2.0 Hz,1H), 6.72 (dd, J=8.2, 1.9 Hz, 1H), 5.57 (s, 2H), 4.69 (t, J=7.7 Hz, 1H),4.05-3.90 (m, 1H), 3.80-3.65 (m, 1H), 3.54-3.41 (m, 1H), 3.20 (s, 3H),2.35-2.10 (m, 5H), 2.00-1.84 (m, 1H), 1.12-0.89 (m, 2H), 0.72-0.52 (m,1H), 0.34 (d, J=7.6 Hz, 2H), −0.07 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.56; MS (ES+) 589.8 (M+Na), MS (ES−) 601.7 (M+Cl); Optical rotation[α]_(D)=(+) 57.23 [0.325, MeOH].

Preparation of(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-amino-4-fluorobenzoyl)-4-methoxypyrrolidine-2-carboxamide(85a)

Reaction of(2R,4R)-N-(3-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-4-methoxypyrrolidine-2-carboxamide(75d) (0.44 g, 0.852 mmol) in DMF (5.0 mL) using DIPEA (0.7 mL, 3.99mmol); EDCI (0.198 g, 1.276 mmol), HOBt (0.195 g, 1.276 mmol) and3-amino-4-fluorobenzoic acid (0.165 g, 1.064 mmol) according to theprocedure as reported in Scheme 82 gave(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-amino-4-fluorobenzoyl)-4-methoxypyrrolidine-2-carboxamide(85a) (0.05 g, 10.7% yield) as off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.61 (s, 1H), 8.52-8.38 (m, 2H), 7.98 (s, 1H), 7.48-7.29 (m,2H), 7.23-6.92 (m, 4H), 6.73 (s, 1H), 5.30 (s, 2H), 4.76-4.60 (m, 1H),4.06-3.87 (m, 1H), 3.80-3.64 (m, 1H), 3.58-3.34 (m, 1H), 3.20 (s, 3H),2.37-2.10 (m, 5H), 2.03-1.82 (m, 1H), 1.11-0.90 (m, 2H), 0.73-0.53 (m,1H), 0.42-0.25 (m, 2H), −0.03-−0.16 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ −128.63, −132.44; MS (ES+) 550.7 (M+1), 572.7 (M+Na), MS (ES−) 548.6(M−1), 584.5 (M+Cl); Optical rotation [α]_(D)=(+) 55.43 [0.35, MeOH].

Preparation of(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-cyanobenzoyl)-4-methoxypyrrolidine-2-carboxamide(86a)

Reaction of(2R,4R)-N-(3-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)phenyl)-4-methoxypyrrolidine-2-carboxamide(75d) (0.7 g, 1.355 mmol) in DMF (10.0 mL) using DIPEA (0.7 mL, 3.99mmol); HATU (0.772 g, 2.032 mmol) and 3-cyanobenzoic acid (0.25 g, 1.693mmol) according to the procedure as reported in Scheme 82 gave(2R,4R)-N-(5-((+)-1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-cyanobenzoyl)-4-methoxypyrrolidine-2-carboxamide(86a) (0.07 g, 22.4% yield) as on off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.62 (s, 1H), 8.44 (d, J=5.7 Hz, 2H), 8.08 (s, 1H), 7.98 (d,J=7.7 Hz, 1H), 7.94-7.80 (m, 3H), 7.69 (t, J=7.8 Hz, 1H), 7.40-7.29 (m,2H), 7.17 (d, J=9.3 Hz, 2H), 4.82-4.65 (m, 1H), 3.99 (t, J=5.7 Hz, 1H),3.69 (dd, J=10.5, 5.9 Hz, 1H), 3.55 (dd, J=10.3, 5.6 Hz, 1H), 3.19 (d,J=1.1 Hz, 3H), 2.33-1.90 (m, 5H), 1.13-0.93 (m, 2H), 0.64 (s, 1H), 0.34(d, J=7.5 Hz, 2H), −0.07 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −127.51;MS (ES+) 542.7 (M+1), MS (ES−) 540.7 (M−1), 576.6 (M+Cl); Opticalrotation [α]_(D)=(+) 49.70 [0.33, MeOH].

Preparation of (2R,4R)-1-(6-chloronaphthalen-2-ylsulfonyl)-N-(5-((S)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(87b) Step-1 Preparation of(2R,4R)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(87a)

To a stirred solution of (2R,4R)-tert-butyl2-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-4-methoxypyrrolidine-1-carboxylate(75c) (1 g, 1.623 mmol) in DCM (20 mL) was added TFA (3 mL) stirred atroom temperature for 3 h and concentrated under vacuum to afford(2R,4R)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(87a) 1.3 g TFA salt as an off-white solid, which was used as such innext step; MS (ES+) 517.3 (M+1), MS (ES−) 515.2 (M−1).

Step-2: Preparation of(2R,4R)-1-(5-chloronaphthalen-1-ylsulfonyl)-N-(5-((+)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(87b)

To a stirred solution of(2R,4R)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(87a) (0.7 g, 1.355 mmol) in DCM (20 mL) was added N,N-diisopropylethylamine (1.2 mL, 6.775 mmol) followed by5-chloronaphthalene-1-sulfonyl chloride (0.354 g, 1.355 mmol) undernitrogen. The reaction mixture was stirred at room temperature for 3 hand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel, eluting with 0-2% methanol in Ethylacetate) to afford (2R,4R)-1-(6-chloronaphthalen-2-ylsulfonyl)-N-(5-((S)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-4-methoxypyrrolidine-2-carboxamide(87b) (0.06 g, 6.96%) as an off white solid. ¹H NMR (300 MHz, DMSO-d₆) δ9.44-9.29 (m, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.49 (d, J=5.2 Hz, 2H),8.32-8.21 (m, 2H), 8.17 (d, J=8.7 Hz, 1H), 8.07-7.95 (m, 2H), 7.73 (dd,J=8.8, 2.2 Hz, 1H), 7.45-7.33 (m, 2H), 7.25-7.11 (m, 2H), 4.39 (dd,J=9.6, 2.9 Hz, 1H), 3.87-3.72 (m, 1H), 3.58 (dd, J=10.5, 2.1 Hz, 1H),3.11 (s, 3H), 2.34-2.07 (m, 3H), 1.97-1.77 (m, 1H), 1.36-1.14 (m, 9H),1.10-1.03 (m, 3H), 0.93-0.59 (m, 2H), 0.49-0.26 (m, 2H), −0.01-−0.10 (m,2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −130.08; MS (ES+): 637.7 (M+1, loss ofsulfinamine group); (ES−) 635.7 (M−1, loss of sulfinamine group), 671.6(M+Cl, loss of sulfinamine group); Optical rotation: [α]_(D)=(+) 83.28[0.305, MeOH].

Example 88

Plasma Kallikrein Activity Assay.

The effect of compounds of the invention on human plasma kallikreinactivity was determined using the chromogenic substrates (DiaPharmaGroup, Inc., West Chester, Ohio, USA). In these experiments, 2 nMkallikrein (Enzyme Research Laboratories, South Bend, Ind., USA) wasincubated with 80 μM S2302 (H-D-Pro-Phe-Arg-p-nitroaniline) in theabsence or presence of increasing concentrations of compounds of theinvention in a final volume of 200 μL Tris-HCl buffer (200 mM NaCl; 2.5mM CaCl₂; 50 mM Tris-HCl, pH 7.8).

After incubation at 30° C., the activity of kallikrein was measured as achange in absorbance at OD 405 nm using BioTek PowerWave X340 MicroplateReader (Winooski, Vt., USA). Data were analyzed using SigmaPlot software(Systat Software, Inc., San Jose, Calif., USA) (Four Parameter LogisticCurve). Ki values for the inhibitors were determined using theCheng-Prusoff equation (Biochem. Pharmacol. 1973, 22, 3099).

The compounds disclosed in this application have Ki values less than 1micromolar (μM) for the plasma kallikrein enzyme. See Table 1.

TABLE 1 Measured Ki values for compounds. Compound Ki (nM) Compound Ki(nM) Compound Ki (nM)  1p >100 17b 50-100 61b <50  2a >100 18b <50 30b50-100  3a 50-100 18a <50 62c <50  4g 50-100 19c >100 63g 50-100 5e >100 33d >100 64g <50  6f >100 20b >100 65b <50  6e >100 21d >10037d <50  7c >100 22b >100 36d >100  8c >100 23b 50-100 31i <50  9c >10024b >100 32a <50 10c >100 25b >100 32b >100 11e >100 26b >100 34d <5013e >100 27b >100 35a 50-100 14h <50 28b >100 66c >100 15f >100 29e <5068a <50 14g >100 30a <50 69a <50 16h >100 60a >100 72c <50 70c <5076e >100 10b >100 71a <50 55a <50  4f 50-100 67b >100 56a <50  9b >10038d <50 77a <50 11d >100 39h <50 57d <50 12b >100 40a <50 41a <5027a >100 47d 50-100 58j <50 29d >100 48d <50 59d <50 33b >100 49d 50-10044e >100 34b >100 52d <50 43m 50-100 81h <50 53d <50 45c >100 79a <5051b <50 46k <50 78a <50 73a <50  5d >100 80c 50-100 74a <50  6d >10082a >100 54g <50  6c >100 83a >100 42l <50  7b >100 84a >100 75e <50 8b >100 85a >100 86a >100 87b >100

EQUIVALENTS

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by examples provided, since theexamples are intended as a single illustration of one aspect of theinvention and other functionally equivalent embodiments are within thescope of the invention. Various modifications of the invention inaddition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description and fall withinthe scope of the appended claims. The advantages and objects of theinvention are not necessarily encompassed by each embodiment of theinvention.

What is claimed is:
 1. A compound represented by Formula (I), or apharmaceutically acceptable salt thereof:

wherein, independently for each occurrence: R¹ represents —OH, —OR^(c),—NH₂, —NHR^(c), —NR^(c)R^(d), alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, halo, haloalkyl, cycloalkyl, (cycloalkyl)alkyl,—C(O)R^(c), —C(O)OH, —C(O)OR^(c), —OC(O)R^(c), —C(O)NH₂, —C(O)NHR^(c),—C(O)NR^(c)R^(d), —NHC(O)R^(c), or —NR^(c)C(O)R^(d); or two geminaloccurrences of R¹ taken together with the carbon to which they areattached represent —C(O)—; or two vicinal or geminal occurrences of R¹taken together form an optionally substituted fused or spirocycliccarbocyclic or heterocyclic ring; W is —C(O)NH- or —C(O)N(R^(c))—; R²represents optionally substituted aryl or heteroaryl; Z is absent orrepresents one or more substituents independently selected from thegroup consisting of halo, haloalkyl, -NO₂, —CN, —C(O)R^(c), —C(O)OH,—C(O)OR^(c), —OC(O)R^(c), —C(O)NH₂, —C(O)NHR^(c), —C(O)NR^(c)R^(d),—NHC(O)R^(c), -N(R^(c))C(O)R^(d), -OS(O)_(p)(R^(c)), —NHS(O)_(p)(R^(c)),and —NR^(c)S(O)_(p)(R^(c)); X represents —C(NH₂)—, —C(NH(R^(c)))—,—C(NR^(c)R^(d))—, —C(NHS(O)_(p)R^(c))—, —C(NHC(O)R^(c))—,—C(NHC(O)NH₂)—, —C(NHC(O)NHR^(c))—, —C(NHC(O)NR^(c)R^(d))—, —C(OH)—,—C(O(alkyl))-, —C(N₃)—, —C(CN)—, —C(NO₂)—, —C(S(O)_(n)R^(a))—,—C[—C(═O)R^(c)]—, —C[—C(═O)NR^(c)R^(d)]-, —C[—C(═O)SR^(c)]—,—C[—S(O)R^(c)]-, —C[—S(O)₂R^(c)]—, —C[S(O)(OR^(c))]—,—C[—S(O)₂(OR^(c))]—, —C[—SO₂NR^(c)R^(d)]—, —C(halogen)-, —C(alkyl),—C((cycloalkyl)alkyl), —C(alkenyl)-, —C(alkynyl)-, or —C(aralkyl)-; R³represents optionally substituted aryl, heteroaryl, cycloalkyl, orheterocycloalkyl; R^(3a) is absent or represents one or moresubstituents independently selected from the group consisting of halo,hydroxy, alkyl, —CF₃, —OCF₃, alkoxy, aryl, heteroaryl, aryloxy, amino,aminoalkyl, —C(O)NH₂, cyano, —NHC(O)alkyl, —SO₂alkyl, —SO₂NH₂,cycloalkyl, —(CH₂)_(r)OR^(a), —NO₂, —(CH₂)_(r)NR^(a)R^(b),—(CH₂)_(r)C(O)R^(a), —NR^(a)C(O)R^(b), —C(O)NR^(c)R^(d),—NR^(a)C(O)NR^(c)R^(d), —C(═NR^(a))NR^(c)R^(d),—NHC(═NR^(a))NR^(c)R^(d), —NR^(a)R^(b), —SO₂NR^(c)R^(d),—NR^(a)SO₂NR^(c)R^(d), —NR^(a)SO₂alkyl, —NR^(a)SO₂R^(a), —S(O)_(p)R^(a),—(CF₂)_(r)CF₃, —NHCH₂R^(a), —OCH₂R^(a), —SCH₂R^(a),—NH(CH₂)₂(CH₂)_(r)R^(a), —O(CH₂)₂(CH₂)_(r)R^(a), or—S(CH₂)₂(CH₂)_(r)R^(a); Y represents a bond; or —Y—R⁴ representsoptionally substituted -alkylene-R⁴, —CH₂C(O)—R⁴, —CH₂NH—R⁴,—CH₂N(alkyl)-R⁴, —CR^(a)R^(b)—R⁴, —NH—R⁴, —NHCH₂—R⁴, —NHC(O)—R⁴,—N(alkyl)-R⁴, —N(alkyl)CH₂-R⁴, —N((CH₂)₂OH)—R⁴, —N((cycloalkyl)alkyl)R⁴,-heterocyclyl-R⁴, —OR⁴, —OCH₂—R⁴, —OC(O)—R⁴, —OC(O)NR^(a)R^(b), —SCH₂R⁴,or —SR⁴; R⁴ represents hydrogen, hydroxy, optionally substituted alkyl,cycloalkyl, (heterocycloalkyl)alkyl, (cycloalkyl)alkyl, —CH₂OH,—CH(alkyl)OH, —CH(NH₂)CH(alkyl)₂, aryl, aralkyl, heteroaryl,heteroaralkyl, —CH₂S(alkyl), amino, or cyano; or—(CR^(a)R^(b))_(r)(CR^(a)R^(b))_(p)— fused to the 4-position of the ringbearing Z to form a 5- to 7-membered heterocyclic ring with optionalsubstituents; or, when R³ is phenyl, R⁴ can represent —NR^(a)— fused tothe position ortho to X on that phenyl; each R^(a) and R^(b) isindependently H, alkyl, alkenyl, alkynyl, aralkyl, (cycloalkyl)alkyl,—C(═O)R^(c), —C(═O)OR^(c), —C(═O)NR^(c)R^(d), —C(═O)SR^(c), —S(O)R^(c),—S(O)₂R^(c), —S(O)(OR^(c)), or —SO₂NR^(c)R^(d); R^(c) and R^(d)represent, independently for each occurrence, optionally substitutedalkyl, alkenyl, alkynyl, haloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,(heterocycloalkyl)alkyl, —C(O)alkyl, or —S(O)_(p)(alkyl); or R^(c) andR^(d) can be taken together to form an optionally substitutedheterocyclic ring;

can represent

r is 0, 1, 2, or 3; n is an integer from 0 to 6; and p is 0, 1, or
 2. 2.The compound of claim 1, wherein R¹ represents —OH, —OR^(c), —NH₂,—NHR^(c), —NR^(c)R^(d), alkyl, aryl, heteroaryl, halo, haloalkyl,cycloalkyl, —OC(O)R^(c), —NHC(O)R^(c), or —NR^(c)C(O)R^(d); or twogeminal occurrences of R¹ taken together with the carbon to which theyare attached represent —C(O)—; or two vicinal or geminal occurrences ofR¹ taken together form an optionally substituted fused or spirocycliccarbocyclic or heterocyclic ring.
 3. The compound of claim 2, wherein R¹represents —OH, —OR^(c), —NH₂, alkyl, aryl, halo, haloalkyl, cycloalkyl,or —OC(O)R; and n is 1 or
 2. 4. The compound of claim 3, wherein n is 1;and R¹ represents —OH, -O((C₁-C₆)alkyl), —OC(O)((C₁-C₆)alkyl), —NH₂, or(C₁-C₆)alkyl.
 5. The compound of claim 3, wherein n is 2; and the twooccurrences of R¹ are geminal.
 6. The compound of claim 5, wherein: (a)one occurrence of R¹ represents —OH or —OR^(c); and the other occurrenceof R¹ represents aryl or heteroaryl; (b) one occurrence of R¹ represents—OH or —OR^(c); and the other occurrence of R¹ represents haloalkyl; (c)both occurrences of R¹ are halo; or (d) the two geminal occurrences ofR¹ taken together with the carbon to which they are attached represent—C(O)—.
 7. The compound of claim 3, wherein n is 2; the two occurrencesof R¹ are vicinal; and the two vicinal occurrences of R¹ taken togetherform an optionally substituted fused carbocyclic ring.
 8. The compoundof claim 1, wherein R² represents aryl or heteroaryl, substituted by oneor more substituents selected from the group consisting of —OH, halo,—NH₂, —NH((C₁-C₆)alkyl), —N((C₁-C₆)alkyl)₂, —CN, —NO₂, (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, —C(O)OH, —C(O)O(C₁-C₆)alkyl, —C(O)NH₂,—C(O)NH(C₁-C₆)alkyl, and —C(O)N((C₁-C₆)alkyl)₂.
 9. The compound of claim1, wherein V represents optionally substituted aryl.
 10. The compound ofclaim 1, wherein Z is absent, or wherein Z represents one or moresubstituents independently selected from the group consisting of halo,haloalkyl, —NO₂, and —CN.
 11. The compound of claim 10, wherein Zrepresents one instance of halo.
 12. The compound of claim 1, wherein Xrepresents —C(NH₂)—, —C(NH(R^(c)))—,—C(NR^(c)R^(d))—,—C(NHS(O)_(p)R^(c))—, —C(NHC(O)R^(c))—, —C(NHC(O)NH₂)—,—C(NHC(O)NHR^(c))—, or —C(NHC(O)NR^(c)R^(d))—.
 13. The compound of claim12, wherein X represents —C(NH₂)—; —C(NH(cycloalkyl)alkyl)-;—C(NH(C₁-C₆)alkyl)-; —C(NHS(O)_(p)(C₁-C₆)alkyl)-, wherein p is 1 or 2;optionally substituted —C(NHC(O)NH(aryl))-; optionally substitutedC(NHC(O)NH(heteroaryl))-; or —C(NHC(O)((C₁-C₆)alkyl))-.
 14. The compoundof claim 1, wherein R³ represents optionally substituted aryl oroptionally substituted heteroaryl.
 15. The compound of claim 14, whereinR³ represents phenyl, optionally substituted by one or more substituentsselected from the group consisting of —CN, halo, —NO₂, (C₁-C₆)alkyl, and(C₁-C₆)haloalkyl; or wherein R³ represents pyridyl.
 16. The compound ofclaim 1, wherein R^(3a) is absent or represents halo, alkyl, —CF₃,—OCF₃, aryl, heteroaryl, —C(O)NH₂, cyano, —NHC(O)alkyl, —SO₂alkyl,—SO₂NH₂, —NO₂, —NR^(a)C(O)R^(b), —C(O)NR^(c)R^(d),—NR^(a)C(O)NR^(c)R^(d), —C(═NR^(a))NR^(c)R^(d),—NHC(═NR^(a))NR^(c)R^(d), —SO₂NR^(c)R^(d), —NR^(a)SO₂NR^(c)R^(d),—NR^(a)SO₂alkyl, —NR^(a)SO₂R^(a), —S(O)_(p)R^(a), or —(CF₂)_(r)CF₃. 17.The compound of claim 1, wherein Y represents a bond.
 18. The compoundof claim 1, wherein R⁴ represents H, (cycloalkyl)alkyl, or(cyclopropyl)(C₁-C₆)alkyl.
 19. The compound of claim 1, selected fromthe following table:


20. A pharmaceutical composition, comprising a compound of claim 1, or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.
 21. A pharmaceutical composition, comprising acompound of claim 19, or a pharmaceutically acceptable salt thereof; anda pharmaceutically acceptable carrier.
 22. The compound of claim 8wherein R2 represents (halo)aryl or (halo)heteroaryl.
 23. The compoundof claim 11 wherein Z represents one instance of fluoro.